WO1997032832A1

WO1997032832A1 - Process for producing fluorinated aromatics and fluorinated nitrogen-containing hetero-aromatics

Info

Publication number: WO1997032832A1
Application number: PCT/EP1997/000970
Authority: WO
Inventors: Wolfgang Appel; Sergej Pasenok; Hans-Jerg Kleiner
Original assignee: Hoechst Research & Technology Deutschland Gmbh & Co. Kg
Priority date: 1996-03-07
Filing date: 1997-02-28
Publication date: 1997-09-12
Also published as: CA2248294A1; EP0885179A1; CN1212674A; DE19608791A1; JP2000506149A; KR19990087687A

Abstract

The production of fluorinated aromatic compounds of general formula (I), in which W, X, Z, R1 and R2 have the meanings given in the description, from corresponding C1 or Br-containing compounds with fluorides, e.g. KF, with halogen exchange in a reaction medium, is known. According to the invention, the 'halex' reaction (exchange of a halogen for fluorine) is performed in a reaction medium containing compounds of general formula (III), (IV) and/or (V) in which R?16 to R24¿ have the meaning given in the description. This provides a particularly advantageous process in which gentler conditions may be applied while providing higher output and fewer by-products. Fluorinated aromatic compounds of formula (I), e.g. are used as intermediate products for active agent synthesis.

Description

description

Process for the preparation of fluorinated aromatics and fluorinated nitrogen-containing heteroaromatics

The invention relates to a process for the preparation of fluorinated aromatic compounds of the general formula I.

wherein

Is WN or CR ³ ,

Is XN or CR ⁴ ,

Is YN or CR ⁵ ,

Is ZN or CR ⁶ ,

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , the same or different, hydrogen, F, Cl, Br, J, NO ₂ , CF ₃ , CN, CHO, COF, SO ₂ F, SO ₂ CI, OCF ₃ , SCF ₃ , SO ₂ CF ₃ , COOR ⁷ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ^{1 1} or OR ¹² or two residues from the group R ¹ to R ⁶ located in the ortho position to one another together are -OC-NR ¹³ -CO-,

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , the same or different, independently of one another, hydrogen, C 1 -C 6 -alkyl, linear or branched, aryl, preferably phenyl, or arylalkyl, and both the alkyl radicals and the arylalkyl radicals can optionally be substituted up to three times with halogen, preferably CF ₃ and CHal _x H ₃ . _x can be, and optionally two or more of the radicals R ¹ to R ^{13 are} joined together to form one or more rings, it being possible for the ring or rings to have 3 to 7 ring members,

with the provisos that

(i) W, X and Y must not be N at the same time;

(ii) at least one of R ¹ to R ⁶ must be fluorine; and

(iii) a) in the event that the compound of the formula I is an aromatic mononuclear halogenated compound, at least one of the remaining radicals from the

Group R ¹ to R ⁶ NO ₂ , CF ₃ , CN, CHO, COOH, COCI, COF, SO ₂ F, SO ₂ CI, SO ₂ CF ₃ ,

CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ ; and b) in the event that the compound of the formula I is an aromatic multi-core halogenated compound, preferably having 3 halogen substituents on the aromatic nucleus, the remaining radicals from the group R ¹ to R ^{6 may} all be hydrogen,

by reaction of compounds corresponding to formula I, but in which the radicals R ¹ to R ⁶ which must be fluorine in formula I is Cl or Br,

with fluorides of the general formula II

MeF (II) where Me is Na, K, Cs, Rb, N (R ¹⁴ ) ₄ or P (R ¹⁵ ) ₄ ,

where the four R ¹⁴ radicals, independently of one another, may be the same or different hydrogen, C 1 -C ₈ -alkyl, linear or branched, the alkyl radicals in turn being able to be substituted, for example, with aromatic radicals; and the four R ¹⁵ radicals, independently of one another, the same or different, can have the meaning of R ¹⁴ and can also be phenyl; in a reaction medium. The substitution of aromatically bound hydrogen by fluorine is of great importance for the synthesis of bioactive substances or for the preparation of precursors to such compounds. Furthermore, it is well known that fluorine has strong and often unexpected effects on the biological activity of chemical compounds. The exchange of hydrogen for fluorine in a biologically active molecule often leads to an analogue compound with an increased or modified biological effect.

In addition to direct fluorination, the production of fluoroaromatics by exchanging a halogen (Cl, Br) for fluorine (so-called "halex process") is an extremely valuable reaction which is of great industrial importance.

For more detailed state of the art, the

D1 = Finger et al., J. Am. Chem. Soc. 87 (1965) 430,

D2 = DE-A 27 24 367,

D3 = EP-A-0 164619,

D4 = Dmowski et al., J. Fluor. Chem., 41 (2) (1988) 241,

D5 = Banks et al., J. Fluor. Chem., 46 (1990) 529,

D6 = Clark et al., Tetrahedron Lett., 28 (1987), 111,

D7 = Deutsch et al., Synth. Chem., 55 (1991), 335,

D8 = JP-A-87 105 097,

D9 = JP-A-90 83 364,

D10 = Pews et al., J. Fluor., Chem., 50 (1990) 365 ff.,

D11 = CA 105: 60401 c for JP 61 50945,

D12 = CA 104: 129611 v to JP 60237 051,

D13 = CA 115: 135672j for JP 03 077-850 A,

D14 = CA 109: 92482d to DE 36 37 156 and

D15 = CA 113: 175049b for JP 02 111-624

called. Patents and publications D1 to D5 generally describe the production of fluoroaromatics by directly exchanging halogen atoms with KF, CsF or (Alk) ₄ N ⁺ F ^" . However, because of the high cost of CsF or (Alk) ₄ N ⁺ F ^" Industrial time only used KF. However, its use has a number of serious disadvantages.

The solubility of KF in most aprotic organic solvents is generally very low and is in the range of about 10 ^"3 mol / l or less. This means a low concentration of fluoride ions in solution and leads to de facto long reaction times, one high energy consumption and high equipment costs, and there is also a need to work at high temperatures, which often leads to the formation of by-products.

The Cl-F exchange usually takes place at activated aromatics at temperatures in the range of about 100 to 200 ° C and at non-activated aromatics at temperatures in the range of about 250 to 400 ° C. In the case of slightly or not activated aromatics, particularly drastic reaction conditions are necessary (cf. D10), with numerous by-products being formed. The reactions can be carried out in a solvent or without solvent. However, the best results can be achieved using aprotic, highly polar solvents as the reaction medium.

Acetonitrile (CH ₃ CN), dimethylformamide (DMFA), dimethylacetamide (DMAA), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), tetramethylene sulfone (sulfolane or TMS), hexamethylphosphoric triamide (HMPA), pyridylonitrile (pyridylonitrile) were used as solvents (PhCN) used.

Because of their low boiling points (80 ° C and 150 ° C), CH ₃ CN and DMFA are only suitable for the exchange of highly activated halogen atoms. High yields of fluorine-containing products are often achieved using DMSO as a solvent, the excellent solubility of which is known for inorganic salts. However, the low thermal stability of DMSO leads to destruction in (CH ₃ ) ₂ S and (CH ₃ ) SO ₂ . These decomposition products in turn lead to one correspondingly strong and if possible avoidable odor pollution.

In general, the rate of fluorination with KF on the same substrate increases depending on the solvent as follows: acetonitrile (CH ₃ CN) - N-methylpyrrolidone (NMP) - tetramethylene sulfone (sulfolane) - dimethyl sulfoxide (DMSO) (see D6).

(HMPA) shows excellent properties as a solvent for Halex reactions, but because of its toxicity for industrial processes it is out of the question.

To increase the solubility of KF in the reaction mixture and accordingly to improve its fluorination activity, numerous catalysts have been used. The D7 propagates the addition of crown ethers or polyethylene glycol (PEG), while the D8 and D9 suggest the addition of ammonium or phosphonium salts. However, adding catalysts generally means higher costs. Additional wastewater pollution is caused and the additives often do not catalyze satisfactorily.

In view of the prior art specified and discussed herein, it was therefore an object of the invention to provide a method of the type mentioned at the outset which allows the production of defined target compounds in good yield with high selectivity. The new process should be suitable for large-scale use, be as little polluting as possible and at the same time be inexpensive to implement with relatively simple means. The method should in particular be as free as possible from the disadvantages mentioned above, which have hitherto been inherent in the methods available in the prior art.

These and other tasks not specified are solved by a method of the type mentioned at the outset with the feature of the characterizing part of claim 1. Expedient modifications of the method of the invention are protected in the dependent claims dependent on claim 1. A use belonging to the invention is the subject of claims 11 and 12. Characterized in that the fluorination by halogen exchange in a reaction medium containing 1-alkyl-2,3-dihydro-1H-phosphol-1-oxides of the general formula III, 1-alkyl-2,5-dihydro-1 H-phosphol-1 - oxides of the general formula IV and / or 1-alkylphospholan-1-oxides of the general formula V,

wherein

R ^{16 is} an alkyl radical with 1 to 8 carbon atoms, which can be linear or branched, phenyl, benzyl, cycloalkyl, OR ²⁵ or NR ²⁶ R ²⁷ , where R ²⁵ to R ^27, independently of one another, identically or differently, are an alkyl radical with 1 mean up to 4 carbon atoms, which can be linear or branched, and

R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ independently of one another, identically or differently, denote hydrogen, phenyl or a C 1-6 alkyl radical, linear or branched,

is carried out, it is particularly advantageous to provide a method 7 which improves the known processes both in terms of selectivity, the yield and the quality of the resulting process products in a manner which is not readily predictable.

It has surprisingly been found that when the compounds of the general formulas III, IV and / or V known per se in the literature are used as solvents, a strong acceleration of the reaction can occur, as a result of which the Halex reaction is carried out at a considerably lower temperature and thus under considerably gentler conditions can than was previously possible. This also suppresses or completely avoids the formation of by-products

In particular, the method of the invention has the following advantages.

The compounds of the general formulas III to V are high-boiling, thermally stable, non-toxic or only slightly toxic liquids.

At the same time, the solubility of, for example, KF in reaction media of the general formulas III to V is substantially better, especially at elevated temperatures, than in TMS, NMP, DMAA and comparable to DMSO, so that the fluorination of aromatics takes place completely without any great technical effort by means of halogen exchange and the response time and energy consumption are reduced

In addition, the thermal resistance of compounds of the general formulas III to V is significantly higher in comparison with DMSO, which is known and frequently used, for example, in the prior art. After 7 days at 250 ° C., a maximum of 1.4% carbonaceous decomposition products are found if the compound of the general formula V with R ¹⁷ to R ²⁴ = hydrogen and R ¹⁶ = methyl is used

Among other things, the use of compounds of the general formulas III to V in or as reaction media for the Halex reaction is seen as a whole environmentally friendly chemical process.

Finally, the compounds of the general formulas III to V cover a broad spectrum of boiling points, so that by selecting a suitable compound depending on the boiling point of the expected target product, in almost all cases the reaction mixture can be worked up after the fluorination by separating the reaction mixture by distillation .

This also makes it possible to isolate the compounds of the general formulas III to V and, if desired, to recycle them.

In the context of the invention, the compounds of the general formulas III to V can already provide these advantages if they are present in reaction media for the Halex reaction. That is, they are an addition to an otherwise common reaction medium for fluorination by halogen exchange. In this way, the advantages of the invention can already be achieved. The proportion of compound of the general formulas III to V is variable, since even small additives are able to ensure a positive influence on the Halex reaction. The proportion of compounds of the general formulas III to V which is present in the reaction medium according to the invention is preferably 1.0 to 100 mol%, in particular 5.0 to 80 mol% and particularly preferably 10 to 60 mol%, based on the compound corresponding to formula I, but in which the radical R ¹ to R ⁶ which is fluorine in formula I is Cl or Br.

A proportion of more than 50% by weight (wt / wt) based on the total weight of the reaction medium is particularly expedient.

In a particular process variant, however, it is preferred to use 1-alkyl-2,3-dihydro-1H-phosphol-1 oxides of the general formula III, 1-alkyl-2,5-dihydro-1 H-phosphol-1 oxides of the general formula Formula IV and / or 1-alkyl-phospholan-1-oxides of the general formula V to be used as the reaction medium for the Halex reaction. This means that the major part of the reaction medium through the mentioned connections is formed. Then the advantages according to the invention are particularly pronounced. Secondary quantities of other solvents or diluents are not excluded, but their addition is limited to small proportions (<10 wt% (wt / wt)).

The 1-alkyl-2,3-dihydro-1 H-phosphol-1-oxides of the general formula III, 1-alkyl-2,5-dihydro-1 H-phosphol-1-oxides, which are suitable according to the invention as diluents or solvents of the general formula IV and / or 1-alkylphospholan-1-oxides of the general formula V are for the most part commercially available and thus available. Compounds of the general formulas III to V which are not commercially available can be synthesized in a simple manner by processes familiar to the person skilled in the art. Examples of syntheses can be found, inter alia, in DE-A 2826621 or DE-A 35 14451.

For example, a particularly preferred production route for 1-methyl-2,5-dihydro-1 H-phosphol-1-oxide (compound IVa) starts from butadiene and proceeds according to the following reaction sketch 1:

Reaction sketch 1

Further exemplary routes for the preparation of compounds of the general formulas III to V start with ethylene oxide (cf. reaction sketch 2).

O

PCI- -r> CI ₂ POCH ₂ CH ₂ CI / ~ \

Reaction sketch 2 ⁹

o o

O

As already mentioned, the reaction media mentioned can be used as a diluent, solvent or additive to such agents. The compounds according to the invention can be used in pure form or in a mixture of more than one compound.

The various compounds belonging to the general formulas III to V have different boiling points. Depending on the boiling point of the aromatic starting materials and products and depending on the desired product work-up, a compound tailored to each individual case or an optimal mixture of several compounds of the formulas III to V can be selected, be it as an additive to other reaction media or as a pure reaction medium Form or in a mixture.

Compounds to be used preferably according to the invention include, among others

1-methyl-2,3-dihydro-1 H-phosphol-1-oxide,

1-ethyl-2,3-dihydro-1 H-phosphol-1 oxide,

1-n-propyl-2,3-dihydro-1 H-phosphol-1 oxide,

1-iso-propyl-2,3-dihydro-1H-phosphol-1-oxide,

1-n-butyl-2,3-dihydro-1 H-phosphol-1 oxide,

1-isobutyl-2,3-dihydro-1 H-phosphol-1 oxide, 1-sec-butyl-2,3-dihydro-1 H-phosphol-1 oxide,

1-n-pentyl-2,3-dihydro-1H-phosphol-1-oxide,

1-n-hexyl-2,3-dihydro-1 H-phosphol-1-oxide,

1-methyl-2,5-dihydro-1 H-phosphol-1-oxide,

1-ethyl-2,5-dihydro-1 H-phosphol-1 oxide,

1-n-propyl-2,5-dihydro-1 H-phosphol-1 oxide,

1-isopropyl-2,5-dihydro-1 H-phosphol-1 oxide,

1-n-butyl-2,5-dihydro-1H-phosphol-1-oxide,

1-iso-butyl-2,5-dihydro-1H-phosphol-1-oxide,

1-sec-butyl-2,5-dihydro-1 H-phosphol-1 oxide,

1-n-pentyl-2,5-dihydro-1 H-phosphol-1-oxide,

1-n-hexyl-2,5-dihydro-1 H-phosphol-1-oxide,

1-methyl-phospholan-1-oxide,

1-ethyl-phospholan-1-oxide,

1-n-propyl-phospholan-1-oxide,

1-iso-propyl-phospholan-1-oxide,

1-n-butyl-phospholan-1-oxide,

1-isobutyl-phospholan-1-oxide,

1-sec-butyl-phospholan-1-oxide,

1-tert-butyl-phospholan-1-oxide,

1-n-pentyl-phospholan-1-oxide,

1-neo-pentyl-phospholan-1-oxide,

1-n-hexyl-phospholan-1-oxide,

1-n-heptyl-phospholan-1-oxide,

1-n-octyl-phospholan-1-oxide,

1-dimethylamino-phospholan-1-oxide,

1 -Diethylamino-phospholan-1-oxide, and / or

1-phenoxy-phospholan-1 oxide.

Particularly preferred among the compounds of the general formulas III to V in the context of the invention are 1-methyl-2,3-dihydro-1 H-phosphol-1-oxide (same as purple), 1-methyl-2,5-dihydro- 1 H-phosphol-1-oxide (same as compound IVa) and / or 1-methyl-phospholan-1-oxide (same as compound Va), ie it is advantageous Fluorination is carried out by halogen exchange in one or more compounds of the general formulas III, IV and / or V, in which R ^{16 is} methyl and R ¹⁷ to R ^{24 are} hydrogen.

In a particularly expedient manner, the process according to the invention is further modified in such a way that the fluorination is carried out by halogen exchange in 1-alkylphospholan-1-oxides of the general formula V; 1-methyl-phospholan-1-oxide (same as compound Va).

The process according to the invention is applicable to a large number of compounds corresponding to the general formula I, in which case also substrates which include structures of the formula I as an aromatic subunit in a larger molecule are to be counted.

In an expedient modification of the process, compounds of the general formula VI

wherein

R ¹ 'to R ^{5', the} same or different, hydrogen, F, Cl, Br, J, NO ₂ , CF ₃ , CN, CHO, COF, SO ₂ F, SO ₂ CI, OCF ₃ , SCF ₃ , SO ₂ CF. ₃ , COOR ⁷ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ or OR ¹² or two radicals from the group R ¹ 'to R ⁵ ' which are located in the ortho position to one another are together -OC-NR ¹³ -CO- , with R ⁷ to R ¹³ as in formula I, where, in the event that the compound of the formula VI is an aromatic mono-halogenated compound, at least one of the radicals from the group R ¹ to R ^{5 '} NO ₂ , CF ₃ , CN, CHO, COOH, COCI, COF, SO ₂ F, SO ₂ CI, SO ₂ CF ₃ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ ; and in the event that the compound of the formula VI is an aromatic multi-nuclear halogenated, preferably having 3 halogen substituents on the aromatic nucleus, the remaining radicals the groups R ¹ to R ^{5 may} all be hydrogen,

from compounds of the general formula VII

wherein

Shark represents Cl or Br and R ^{1 '} to R ⁵ ' have the meaning given for formula VI

According to the invention, compounds of the general formula VIII are also used with good success

^w

wherein

R ^{1 '} to R ^{4', the} same or different, hydrogen, F, Cl, Br, J, NO ₂ , CF ₃ , CN, CHO, COF, SO ₂ F, SO ₂ CI, OCF ₃ , SCF ₃ , SO ₂ CF. ₃ , COOR ⁷ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ or OR ¹² or two radicals from the group R ^{1 '} to R ^4' which are in the ortho position to one another are together -OC-NR ¹³ -CO- , with R ⁷ to R ¹³ as in formula I, wherein, in the event that the compound of the formula VIII is a heteroaromatic mononuclear halogenated compound, at least one of the radicals from the group R ^{1 '} to R ^4' NO ₂ , CF ₃ , CN, CHO, COOH, COCI, COF, SO ₂ F, SO ₂ CI, SO ₂ CF ₃ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ , and in the event that the compound of the formula VIII a heteroaromatic multi-nuclear halogen, preferably 3 Halogen compound on the aromatic nucleus, is compound, the remaining radicals from the group R ¹ to R ^{4 may} all be hydrogen,

from the corresponding chlorinated or brominated compounds of the general formula IX

K

wherein

R ^{1 '} to R ^{4' have} the same meaning as in formula VIII and shark stands for Cl or Br.

Finally, in a particularly preferred embodiment, the process according to the invention can also be used to prepare compounds of the general formula X, XI and XII or XIII

^H

(XIII),

wherein

R ^{1 '} to R ^{3' are the} same or different, hydrogen, F, Cl, Br, J, NO ₂ , CF ₃ , CN, CHO, COF, SO ₂ F, SO ₂ CI, OCF ₃ , SCF ₃ , SO ₂ CF. ₃ , COOR ⁷ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ or OR ¹² or, where possible, two radicals from the group R ^{1 '} to R ^3' located in the ortho position to one another together -OC-NR ¹³ Are -CO-, with R ⁷ to R ¹³ as in formula I,

from the corresponding chlorinated or brominated compounds of the general formulas Xa, Xla and Xlla or Xllla

(Xllla),

wherein

R ^{1 '} to R ^{3' have} the meaning given in the formulas X to XIII and shark stands for Cl or Br.

Especially with the nitrogen-containing heteroaromatics, such as the Pyridine derivatives of the formula VIII understand that those fluorinated aromatics can also be successfully produced which are part of a larger molecular assembly, as can be indicated by the following formula Villa:

(Villa),

wherein the radicals R ^'have the meaning given in formula VIII.

It is further preferred in the context of the process according to the invention that the fluorination by halogen exchange is carried out at temperatures in the range from about room temperature to the boiling point of the reaction medium or the starting materials, which correspond to compounds of the general formula I, depending on which boiling point is lower . In comparison with the processes known to date, it should be emphasized in particular that the temperatures can usually be kept lower without sacrificing the speed of the reaction.

In an expedient embodiment, the Halex process according to the invention is characterized in that the fluorination is carried out by halogen exchange at temperatures in the range from about 40 ° C. to about 270 ° C. In a particularly preferred modification, the reaction temperatures are in the range from about 60 ° C. to about 220 ° C.

The fluorinating agents which can be used according to the invention basically include all compounds of the formula II (MeF) in which Me represents an alkali metal, ammonium, phosphonium or an alkylammonium or alkyl or arylphosphonium radical derived from ammonium or phosphonium. Compounds such as sodium fluoride, potassium fluoride, cesium fluoride, tetramethylammonium fluoride and other tetraalkylammonium fluorides in which Alkyl represents ethyl, n-propyl, n-butyl. Tetraphenylphosphoium fluoride is also particularly useful. Of the fluorine-providing compounds of the general formula II (MeF) which can be used successfully in the context of the invention, however, potassium fluoride is particularly preferred because of its low price.

The fluorinating agents are used in an amount sufficient to achieve the desired level of halogen exchange. Their stoichiometric use is preferred, based on the amount of the starting compound which corresponds to the compound of the formula I. Use in excess is also preferred, particularly preferably 1.1 to 2.0 times the molar amount based on the mol of the halogen atoms to be replaced in the starting compound or compounds.

The efficiency of the reaction media used according to the invention, which is particularly high per se, can optionally be further improved by adding catalytically active compounds. In general, all the expert can do this for. B. from the references cited known catalysts. The catalysts which can be used include (R ^" ) ₄ N ⁺ Hal ^" with shark equal to Cl or Br and R ^" equal to C _r C ₄ alkyl, linear or branched; (R ^'" ) ₄ P ⁺ Hal ^" with shark equal Cl or Br and R ^'" equal to C _r C ₄ alkyl, linear or branched, or aryl, preferably phenyl; Crown ether; Polyethylene glycols and / or pyridinium salts. The process of the invention is particularly advantageous with the addition of catalytically effective amounts of tetramethylammonium chloride, tetrabutylammonium chloride, tetraphenylphosphonium bromide, 18-crown-6, PEG and / or R ²⁸ R ²⁹ Np-pyridinium-R ³⁰ , in which R ²⁸ to R ³⁰ preferably an alkyl radical mean with 1 to 8 carbon atoms, which can be linear or branched.

The work-up of the reaction mixture after the fluorination can, as already indicated, advantageously be carried out by separating the reaction mixture by distillation and enables the solvents to be isolated and recycled. For aqueous work-up, the mixture is poured into an excess of water and the products obtained are filtered off or extracted with organic solvents. The extraction of the compounds of the general formulas III to V can be carried out in a simple manner and completely from reaction solutions in perforators continuously with dichloromethane or trichloromethane.

According to the procedure according to the invention, the desired target products are obtained with extraordinary purity. For example, products with a degree of purity of the crude product> 90% are generally available according to the procedure described here. It is noteworthy, for example, that, apart from the compounds of the general formulas III to V, it is hardly possible to extract any impurities and that, after the solvent has been stripped off, crude products which are> 95% pure are obtained.

The invention also relates to the use of 1-alkyl-2,3-dihydro-1H-phosphol-1-oxides of the general formula III, 1-alkyl-2,5-dihydro-1H-phosphol-1-oxides of the general formula IV and / or 1-alkyl-phospholan-1-oxides of the general formula V,

A

wherein

R ^{16 is} an alkyl radical with 1 to 8 carbon atoms, which can be linear or branched, phenyl, Is benzyl, cycloalkyl, OR ²⁵ or NR ²⁶ R ²⁷ , where R ²⁵ to R ^27, independently of one another, identically or differently, denote an alkyl radical having 1 to 4 carbon atoms, which may be linear or branched, and

R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ independently of one another, identically or differently, denote hydrogen, phenyl or a C 1-4 alkyl radical, linear or branched,

as a reaction medium, diluent, solvent or addition to such media and agents to the starting compounds in the preparation of fluorinated aromatic compounds of the general formula I.

wherein

WN or CR ³ , XN or CR ⁴ , YN or CR ⁵ , ZN or CR ⁶ ,

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , the same or different, hydrogen, F, Cl, Br, J, NO ₂ , CF ₃ , CN, CHO, COF, SO ₂ F, SO ₂ CI, OCF ₃ , SCF ₃ , SO ₂ CF ₃ , COOR ⁷ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ or OR ¹² are together or two residues from the group R ¹ to R ⁶ which are in the ortho-position to one another -OC-NR ¹³ -CO-,

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , the same or different, independently of one another hydrogen, C _r C ₆ alkyl, linear or branched, aryl, preferably phenyl, or arylalkyl , and both the alkyl radicals and the arylalkyl radicals can optionally be substituted up to three times with halogen, where they can preferably be CF ₃ and CHal _x H _3.x , and

optionally two or more of the radicals R ¹ to R ^{13 are} joined together to form one or more rings, it being possible for the ring or rings to have 3 to 7 ring members,

with the provisos that

(i) W, X and Y must not be N at the same time; (ii) at least one of R ¹ to R ⁶ must be fluorine; and (iii) a) if the compound of the formula I is an aromatic mononuclear halogenated compound, at least one of the remaining radicals from the group R ¹ to R ⁶ NO ₂ , CF ₃ , CN, CHO, COOH, COCI , COF, SO ₂ F, SO ₂ CI, SO ₂ CF ₃ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ ; and

b) in the event that the compound of the formula I is an aromatic multi-core halogenated compound, preferably having 3 halogen substituents on the aromatic nucleus, the remaining radicals from the group R ¹ to R ^{6 may} all be hydrogen,

by reacting compounds corresponding to formula I, but in which the radicals R ¹ to R ⁶ which must be fluorine in formula I is Cl or Br, with fluorides of the general formula II

MeF (II)

wherein

Me stands for Na, K, Cs, Rb, N (R ¹⁴ ) ₄ or P (R ¹⁵ ) ₄ ,

where the four R ¹⁴ radicals, independently of one another, may be the same or different hydrogen, C ₁ -C ₈ -alkyl, linear or branched, the alkyl radicals in turn being able to be substituted, for example, with aromatic radicals; and the four radicals R ¹⁵ , independently of one another, the same or different, have the meaning of R ¹⁴ and can also be phenyl.

It is very particularly preferred here to use the compounds of the general formulas III to V not only in a reaction medium but as the reaction medium itself, which means without the addition of further diluents or solvents.

The following examples serve to illustrate the subject matter of the invention.

Examples

Examples 1 to 14 and Comparative Examples 1 to 12a

0.1 mol of organic substrates in 50 ml of solvent are placed in a three-necked flask with a thermometer and bubble counter and 0.12 to 0.2 mol of potassium fluoride KF (for each chlorine atom) are added with the exclusion of moisture (N ₂ ). The reaction mixture is heated to a certain temperature and for a certain time (see Table 1). From time to time, samples are taken from the reaction mixture and the progress of the reaction and the conversion are checked by means of gas chromatography. If no more educt can be detected, the reaction mixture is worked up.

For working up, the reaction mixture was poured into an excess of water and the solid constituents were filtered off, optionally extracted with CH ₂ Cl ₂ to obtain liquid products, washed with water and dried. The product mixture obtained can be analyzed with GC, GCMS and ¹⁹ F NMR. The products are further purified by recrystallization from suitable solvents or fractional distillation at atmospheric pressure or under reduced pressure.

Table 1 below gives an overview of the substrates used in the examples, which were used for fluorination by halogen exchange Reaction media, the further reaction conditions, the conversion and the yield of the overall product.

Table 1

Table 1 continued

* 1) = 1-methyl-2,3-dihydro-1H-phosphole-1-oxide compound IIIa = 2 ^*) = 1-methyl-2,5-dihydro-1H-phosphole 1-oxide = compound

IVa 3 ^* ) = 1-methyl-phospholan-1-oxide = compound Va. = Yield

Cf. 1a ^* = comparative example taken from D11 Cf. 1b ^* = comparative example taken from D15, addition of

Tetraphenylphosphonium as catalyst Cf. 5a * = comparative example taken from D12 Cf. 11a ^* = comparative example taken from D13, addition of

Tetraphenylphosphonium as catalyst Cf. 12a ^* = comparative example taken from D14 Example 15

Preparation of 2,4,6-trifluoropyrimidine by reacting 2,4,6-trichloropyrimidine in the presence of 1-methyl-2,3-dihydro-1H-phosphol-1-oxide.

In a 1.5 liter four-necked flask equipped with a thermometer, stirrer and reflux condenser with bubble counter, 183 g (1 mol) of 2,4,6-trichloropyrimidine, 228 g of KF (4 mol) and 20 g (0.17 mol) 1-methyl-2,3-dihydro-1H-phosphol-1-oxide and 400 ml of sulfolane. The mixture is then heated to 100 ° C. for 3 hours with stirring. After the reaction has ended, the product (2,4,6-trifluoropyrimidine) is distilled under reduced pressure into a receiver and then purified by distillation. Conversion 100%, yield 127 g (95%) of theory

Comparative Example 13

Production of 2,4,6-trifluoropyrimidine by reacting 2,4,6-trichloropyrimidine with KF in sulfolane solution.

183 g (1 mol) of 2,4,6-trichloropyrimidine, 228 g (4 mol) of KF and 400 ml of sulfolane are used and the procedure is as described in Example 15. The conversion (based on 2,4,6-trifluoropyrimidine) is 42% (yield 35%).

Further advantages and embodiments of the invention result from the following patent claims.

Claims

Claims:

1. Process for the preparation of fluorinated aromatic compounds of the general formula I

wherein

WN or CR ³ , XN or CR ⁴ , YN or CR ⁵ , ZN or CR ⁶ ,

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , the same or different, independently of one another hydrogen, C _| -C ₆ alkyl, linear or branched, aryl, preferably phenyl, or arylalkyl, and both the alkyl radicals and the arylalkyl radicals can optionally be substituted up to three times with halogen, preferably CF ₃ and CHal _x H _{3. x} can be, and

optionally two or more of the radicals R ¹ to R ^{13 are} joined together to form one or more rings, it being possible for the ring or rings to have 3 to 7 ring members, with the provisos that

b) in the event that the compound of the formula I is an aromatic polynuclear halogenated compound, preferably having 3 halogen substituents on the aromatic nucleus, the remaining radicals from the group R ¹ to R ^{6 may} all be hydrogen,

with fluorides of the general formula II

MeF (II)

wherein

Me stands for Na, K, Cs, Rb, N (R ¹⁴ ) ₄ or P (R ¹⁵ ) ₄ ,

where the four R ¹⁴ radicals, independently of one another, may be the same or different hydrogen, C 1 -C ₈ -alkyl, linear or branched, the alkyl radicals in turn being able to be substituted, for example, with aromatic radicals; and the four R ¹⁵ radicals, independently of one another, the same or different, can have the meaning of R ¹⁴ and can also be phenyl; in a reaction medium

characterized in that the fluorination by halogen exchange in a reaction medium containing 1-alkyl-2,3-dihydro-1H-phosphol-1-oxides of the general formula III, 1-alkyl-2,5-dihydro-1 H-phosphol-1 oxides of the general formula IV and / or 1-alkyl-phospholan-1 oxides of the general formula V,

wherein

is carried out.

2. The method according to claim 1, characterized in that the fluorination by halogen exchange in 1-alkyl-2,3-dihydro-1H-phosphol-1-oxides of the general formula III, 1-alkyl-2,5-dihydro-1 H -phosphol-1-oxides of the general formula IV and / or 1-alkyl-phospholan-1-oxides of the general formula V is carried out as the reaction medium.

3. The method according to claim 1 or 2, characterized in that the fluorination is carried out by halogen exchange in 1-alkyl-phospholan-1-oxides of the general formula V.

4. The method according to one or more of the preceding claims, characterized in that the fluorination is carried out by halogen exchange in one or more compounds of the general formulas III, IV and / or V, in which R ^{16 is} methyl and R ¹⁷ to R ^{24 are} hydrogen.

5. The method according to one or more of the preceding claims, characterized in that compounds of the general formula VI

wherein

R) 1 ¹ '^' K blisr. D R5 ^{0 'the} same or different, hydrogen, F, Cl, Br, J, NO ₂ , CF ₃ , CN, CHO, COF, SO ₂ F, SO ₂ CI, OCF ₃ , SCF ₃ , SO ₂ CF ₃ , COOR ⁷ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ or OR ¹² or two radicals from the group R ¹ 'to R ⁵ ' which are in the ortho position to one another are together -OC-NR ¹³ -CO-, with R ⁷ to R ¹³ as for formula I, where, in the event that the compound of the formula VI is an aromatic mononuclear halogenated compound, at least one of the radicals from the group R ¹ to R ^{5 '} NO ₂ , CF ₃ , CN, Is CHO, COOH, COCI, COF, SO ₂ F, SO ₂ CI, SO ₂ CF ₃ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ ; and in the event that the compound of formula VI is an aromatic multi-core halogenated compound, preferably having 3 halogen substituents on the aromatic nucleus, the remaining radicals from the group R ¹ to R ^{5 may} all be hydrogen,

be produced from the corresponding chlorinated or brominated compounds.

6. The method according to one or more of claims 1 to 4, characterized in that compounds of the general formula VIII

^W

wherein

R ^{1 '} to R ^{4', the} same or different, hydrogen, F, Cl, Br, J, NO ₂ , CF ₃ , CN, CHO, COF, SO ₂ F, SO ₂ CI, OCF ₃ , SCF ₃ , SO ₂ CF. ₃ , COOR ⁷ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ or OR ¹² or two radicals from the group R ^{1 '} to R ^4' which are in the ortho position to one another are together -OC-NR ¹³ -CO- , with R ⁷ to R ¹³ as in formula I, wherein, in the event that the compound of the formula VIII is a heteroaromatic mononuclear halogenated compound, at least one of the radicals from the group R ^{1 '} to R ^4' NO ₂ , CF ₃ , CN, CHO, COOH, COCI, COF, SO ₂ F, SO ₂ CI, SO ₂ CF ₃ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ ; and in the event that the compound of the formula VIII is a heteroaromatic, multi-core halogenated, preferably having 3 halogen substituents on the aromatic nucleus, the remaining radicals from the group R ¹ to R ^{4 may} all be hydrogen, from the corresponding chlorinated or brominated Connections are made.

7. The method according to one or more of claims 1 to 4, characterized in that compounds of the general formula X, XI and XII or XIII

wherein

be produced from the corresponding chlorinated or brominated compounds.

8. The method according to one or more of the preceding claims, characterized in that the fluorination is carried out by halogen exchange at temperatures in the range from about room temperature to the boiling point of the reaction medium or the starting material compound, which corresponds to the compound of general formula I, depending on, which boiling temperature is lower.

9. The method according to claim 8, characterized in that the fluorination is carried out by halogen exchange at temperatures in the range of about 40 ° C to about 270 ° C.

10. The method according to claim 1, characterized in that the reaction medium contains at least one of the compounds of the general formulas III to V in an amount of 1.0 to 100 mol% based on the compound corresponding to formula I, but in which the radicals R ¹ to R ⁶ , which in formula I is fluorine, is Cl or Br.

11. Use of 1-alkyl-2,3-dihydro-1 H-phosphol-1 oxides of the general formula III, 1-alkyl-2,5-dihydro-1H-phosphol-1 oxides of the general formula IV and / or 1-alkyl-phospholan-1-oxides of the general formula V,

wherein

R ^{16 is} an alkyl radical with 1 to 8 C atoms, which can be linear or branched, phenyl, benzyl, cycloalkyl, OR ²⁵ or NR ²⁶ R ²⁷ , where R ²⁵ to R ^27, independently of one another, identically or differently, are an alkyl radical with 1 mean up to 4 carbon atoms, which can be linear or branched, and

_R 17 _R 18 _R 19 _R 20 _R 21 _R 22 _R 2 ³ _R ²⁴ _{independently of} one another, identically or differently, _denote hydrogen, phenyl or a C _1-6 alkyl radical, linear or branched,

as a reaction medium, diluent, solvent or additive to such media and agents for the starting compounds in the preparation of fluorinated aromatic compounds of the general formula I.

wherein

WN or CR ³ , XN or CR ⁴ , YN or CR ⁵ , ZN or CR ⁶ ,

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , the same or different, independently of one another hydrogen, C _r C ₆ alkyl, linear or branched, aryl, preferably phenyl, or arylalkyl , and both the alkyl radicals and the arylalkyl radicals can optionally be substituted up to three times with halogen, preferably CF ₃ and CHal _x H ₃ . _x can be, and

with the provisos that

(i) W, X and Y must not be N at the same time; (ii) at least one of R ¹ to R ⁶ must be fluorine; and (iii) a) in the event that the compound of the formula I is an aromatic mononuclear halogenated compound, at least one of the remaining radicals from the group R ¹ to R ⁶ NO ₂ , CF ₃ , CN, CHO, COOH, COCI , COF, SO ₂ F, SO ₂ CI, SO ₂ CF ₃ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ ; and

b) in the event that the compound of the formula I is an aromatic multi-nucleus halogenated compound, preferably having 3 halogen substituents on the aromatic nucleus, the remaining radicals from the group R ¹ to R ^{6 may} all be hydrogen,

with fluorides of the general formula II

MeF (II)

wherein

Me stands for Na, K, Cs, Rb, N (R ¹⁴ ) ₄ or P (R ¹⁵ ) ₄ ,

where the four R ¹⁴ radicals, independently of one another, may be the same or different hydrogen, C _r C ₈ alkyl, linear or branched, the alkyl radicals can in turn be substituted, for example, with aromatic radicals; and the four radicals R ¹⁵ , independently of one another, the same or different, can have the meaning of R ¹⁴ and can also be phenyl.

12. Use according to claim 11, wherein the compounds of general formulas III to V are used as the reaction medium.