KR19990087687A - Process for preparing fluorinated aromatics and fluorinated nitrogen-containing hetero-aromatics - Google Patents

Abstract

It is known to produce fluorinated aromatic compounds of formula (I) from the corresponding Cl or Br-containing compounds of formula (I) by halogen exchange using fluorides (eg KF) in the reaction medium. According to the invention, a "halex" reaction (substituting halogen with fluorine) is carried out in a reaction medium containing a compound of formula III, IV and / or V. This method can be applied to milder conditions and provides a particularly advantageous method with higher yields and fewer byproducts. Fluorinated aromatic compounds of formula I are used, for example, as intermediate products for the synthesis of active agents.

Formula I

Formula III

Formula IV

Formula V

In the above formula,

W, X, Z, R ¹ , R ² and R ¹⁶ to R ²⁴ have the meanings given in the detailed description of the invention.

Description

Process for preparing fluorinated aromatics and fluorinated nitrogen-containing hetero-aromatics

The present invention corresponds to a compound of formula (I), but reacting a compound wherein ^one of the radicals R ¹ to R ⁶ which is fluorine in formula (I) is Cl or Br with a fluoride of formula (II) in a reaction medium to Relates to a method of making:

MeF

In the above formula,

W is N or CR ³ ,

X is N or CR ⁴ ,

Y is N or CR ⁵ ,

Z is N or CR ⁶ ,

R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and hydrogen, F, Cl, Br, I, NO ₂ , CF ₃ , CN, CHO, COF, SO ₂ F, SO ₂ Cl, OCF ₃ , SCF ₃ , SO ₂ CF ₃ , COOR ⁷ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ or OR ^12, or are in the ortho position relative to one another and derived from groups R ¹ to R ⁶ The two radicals together are —OC—NR ¹³ —CO—,

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are the same or different and independently from each other hydrogen, straight or branched C ₁ to C ₆ -alkyl, aryl, preferably phenyl, Or arylalkyl, the alkyl radical and the arylalkyl radical may be substituted up to three times by halogen if appropriate, preferably CF ₃ and CHal _X H _3-X ,

Two or more of the radicals R ¹ to R ¹³ are suitably linked to one another to form one or more three to seven membered rings,

Provided that (i) W, X and Y are not N at the same time;

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

(iii) a) when the compound of formula (I) is an aromatic mononuclear halogenated compound, at least one of the remaining radicals of groups R ¹ to R ⁶ is NO ₂ , CF ₃ , CN, CHO, COOH, COCl, COF, SO ₂ F, SO ₂ Cl, SO ₂ CF ₃ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ or COR ¹¹ ;

b) when the compound of formula (I) is preferably an aromatic multinuclear halogenated compound having three halogen substituents on the aromatic nucleus, all remaining radicals of groups R ¹ to R ⁶ may be hydrogen;

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

The four radicals R ¹⁴ may be the same or different independently of one another and are hydrogen or straight or branched C ₁ to C ₈ -alkyl, wherein the alkyl radicals may for example be substituted by aromatic radicals, 4 Radicals R ¹⁵ may independently be the same or different and may be the same as R ¹⁴ or be phenyl.

Substitution of aromatic bonded hydrogen with fluorine is very important for the synthesis of bioactive materials and for the preparation of precursors of such compounds. It is also known that fluorine exhibits potent and often unexpected effects on biologically active chemical compounds. Substitution of hydrogen with fluorine in biologically active molecules often results in homologue compounds with increased or modified biological effects.

In addition to direct fluorination, the substitution of halogens (Cl, Br) with fluorine to produce fluorine-containing aromatic compounds (the so-called "halex process") is an extremely useful reaction of great industrial importance.

References to literature most closely related to the art include:

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

D2 = DE-A 27 24 367,

D3 = EP-A-0 164 619,

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) 365ff.,

D11 = CA 105: 60401c to JP 61 50 945,

D12 = CA 104: 129611v to JP 60 237 051,

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

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

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

The patents and patent publications D1 to D5 describe the preparation of fluorine-containing aromatic compounds by direct substitution of halogen atoms using KF, CsF or (alk) ₄ N ⁺ F ⁻ in a general manner. Nevertheless, due to the high cost of CsF or (alk) ₄ N ⁺ F ⁻ , only KF is currently used in industry. However, the use of such compounds has many significant disadvantages.

In general, the solubility of KF in most aprotic organic solvents is very low and ranges up to about 10 ⁻³ mol / l. This results in low concentrations of fluoride ions in solution and in fact leads to long reaction times, high energy consumption and high equipment costs. In addition, high temperatures must be used, often resulting in the formation of dispersions.

Cl → F substitutions typically occur in a temperature range of about 100 to 200 ° C. for activated aromatic compounds and about 250 to 400 ° C. for non-activated aromatic compounds. In particular, for aromatic compounds which are not active or only slightly active, significant reaction conditions (eg D10) are required and a large number of by-products are formed. This reaction can be carried out in the presence or absence of a solvent. However, best results are achieved when aprotic, highly polar solvents are used as the reaction medium.

Examples of solvents include acetonitrile (CH ₃ CN), dimethylformamide (DMFA), dimethylacetamide (DMAA), N-methylpyrrolidone- (NMP), dimethyl sulfoxide (DMSO), tetramethylenesulfone (sulfolane or TMS ), Hexamethylphosphoric triamide (HMPA), pyridylnitrile (PyrCN) or benzonitrile (PhCN) is used.

Due to the low boiling point (80-150 ° C. respectively), only CH ₃ CN and DMFA are suitable for replacing highly activated halogen atoms. High yields of fluorine-containing products are often achieved when using DMSO as a solvent, which is known to have significant solubility of inorganic salts. However, the low thermal stability of DMSO leads to degradation into (CH ₃ ) ₂ S and (CH ₃ ) SO ₂ . These degradation products cause unpleasant odors that should be avoided, possibly accompanied by degradation.

In principle, when using the same base, the rate of fluorination with KF increases with solvent in the following manner:

Acetonitrile (CH ₃ CN) → N-methylpyrrolidone (NMP) → tetramethylenesulfone (sulfolane) → dimethyl sulfoxide (DMSO) (cf. D6).

(HMPA) is a solvent for Harlex reactions but is not suitable for industrial processes due to its toxicity.

Many catalysts have been used to increase the solubility of KF in the reaction mixture and to correspondingly improve the fluorination activity. Thus, Document D7 recommends the addition of crown ethers or polyethylene glycol (PEG), while Documents D8 and D9 suggest addition of ammonium salts and phosphonium salts, respectively. However, the addition of catalysts generally shows higher costs. In addition, it causes contamination of the waste water, and the added catalyst is often not catalyzed in a satisfactory manner.

In view of the prior documents presented and referred to herein, the object of the present invention is typically to specify a method by which the target compounds mentioned and defined above can be prepared with good yield and high selectivity. The novel method of the present invention is to be suitable for large scale industrial applications, to minimize environmental pollution as much as possible, and at the same time to be economical using a relatively simple method. In addition, the method of the present invention is directed to methods currently available in the art so that the above-mentioned disadvantages are in particular maximized.

The object of the present invention, and other objects not specified in detail, are achieved by a method which is constructed in the form mentioned above and which has the features of a particular part of claim 1.

Modifications for convenience of the method of the invention are also protected in the dependent claims according to claim 1. Uses belonging to the invention are the subject of claims 11 and 12.

Fluorination by halogen substitution results in 1-alkyl-2,3-dihydro-1H-phosphol-1-oxide of formula III, 1-alkyl-2,5-dihydro-1H-phosphol-1- of formula IV Due to the fact that it is carried out in a reaction medium containing oxides and / or 1-alkyl-phospholan-1-oxides of the formula V, in an unpredictable manner in terms of the selectivity, yield and properties of the reaction product obtained It is particularly advantageous to provide a method for improving the known method:

In the above formula,

R ¹⁶ is straight or branched alkyl radical of 1 to 8 carbon atoms, phenyl, benzyl, cycloalkyl, OR ²⁵ or NR ²⁶ R ²⁷ , wherein R ²⁵ to R ²⁷ are the same as or different from each other independently and are linear or branched Is an alkyl radical having 1 to 4 carbon atoms),

R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ are independently the same or different from each other and are hydrogen, phenyl or straight or branched C _1-8 -alkyl radicals.

Surprisingly, by the present invention, the use of the compounds of the formulas III, IV and / or V as known in the literature as solvents can strongly accelerate the reaction, resulting in the Halex reaction at substantially lower temperatures, and consequently It has been found that it can be carried out under milder conditions than already possible. This also allows the formation of byproducts to be suppressed or eliminated completely.

In particular, the method of the present invention exhibits the following advantages:

Compounds of Formulas III-V are nontoxic or extremely low toxicity, high thermally stable liquids.

At the same time, for example, the solubility of KF in the reaction medium of formulas III to V is substantially better than that of TMS, NMP or DMAA, especially at elevated temperatures and corresponds to the solubility of DMSO, so that fluorination of aromatic compounds by halogen substitution is highly Complete without sophisticated technology, reaction time and energy consumption are reduced.

In addition to this, the ability of the compounds of formulas III to V to withstand thermal stress is significantly higher than that of DMSO, for example, compounds known and often used in the art. Thus, when a compound of formula V is used wherein R ¹⁷ to R ²⁴ are hydrogen and R ¹⁶ is methyl, up to 1.4% of carbonaceous decomposition products are found after 7 days at 250 ° C.

For this reason, the use of the compounds of the formulas (III) to (V) in or as a reaction medium for the Harlex reaction are all environmentally friendly chemical methods.

Finally, the compounds of the formulas III to V contain a wide range of boiling points, and the reaction mixture is in most cases after fractional distillation of the reaction mixture after fluorination, in particular by selecting a suitable compound according to the predicted boiling point of the desired product. Can be processed.

By these means, it is also possible to separate the compounds of the formulas III to V and optionally recycle them.

Within the scope of the present invention, the compounds of the formulas (III) to (V) already provide these advantages when they are present in the reaction medium for the Halex reaction, i.e. when they constitute a conventional reaction medium for fluorination by halogen substitution. Can be. The advantages of the invention can be achieved in this way. In this context, the proportion of compounds of Formulas III-V is variable because small amounts of additives may have a definite effect on the Halex reaction. The proportion of compounds of the formulas (III) to (V) present in the reaction medium according to the invention corresponds to formula (I) but is preferably 1.0 based on compounds wherein one of the radicals R ¹ to R ⁶ , which is fluorine in formula (I), is Cl or Br To 100 mol%, in particular 5.0 to 80 mol%, and particularly preferably 10 to 60 mol%.

A ratio of at least 50% by weight (wt / wt) based on the total weight of the reaction medium is particularly convenient.

However, in a variant of the specific method, the reaction medium for the Harlex reaction may be 1-alkyl-2,3-dihydro-1H-phosphol-1-oxide of formula III, 1-alkyl-2,5-di of formula IV. Preference is given to using hydro-1H-phosphol-1-oxide and / or 1-alkyl-phospholane-1-oxide of the formula (V). This means that most of the reaction medium is formed by the compound. The advantages according to the invention are particularly significant. Although a small amount of other solvents or dilutions are excluded herein, they may be added in small amounts (less than 10 wt% (wt / wt)).

Most 1-alkyl-2,3-dihydro-1H-phosphol-1-oxides of formula III, 1-alkyl-2,5-dihydro of formula IV suitable for use as diluents or solvents according to the invention -1H-phosphole-1-oxide and / or 1-alkyl-phospholane-1-oxide of formula V can be obtained commercially and used. Compounds of formulas III to V that are not commercially available can be synthesized in a simple manner using methods familiar to those skilled in the art. Examples of synthetic methods are in particular provided in DE-A 28 26 621 or DE-A 35 14 451.

For example, it is particularly preferred to prepare 1-methyl-2,5-dihydro-1H-phosphol-1-oxide (compound of Formula IVa) starting with butadiene and proceeding according to Scheme 1 below:

Another exemplary route for preparing compounds of Formulas III-V starts with ethylene oxide (Scheme 2).

As already mentioned, the reaction medium can be used as a diluent or solvent or as an additive to a diluent or solvent. The novel compounds can be used in pure form or as mixtures of one or more compounds.

Different compounds included in compounds of Formulas III-V have different boiling points. Depending on the boiling point of the aromatic starting compound and the product and the product to be worked up, the optimum mixture of the prepared compound or of several compounds of the formulas (III) to (V) may be prepared as additives to other reaction media or as reaction medium in pure form or as a mixture. May be selected in the case.

Compounds which can preferably be used according to the invention are in particular as follows:

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

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

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

1-isopropyl-2,3-dihydro-1H-phosphol-1-oxide;

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

1-isobutyl-2,3-dihydro-1H-phosphol-1-oxide;

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

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

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

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

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

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

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

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

1-isobutyl-2,5-dihydro-1H-phosphol-1-oxide;

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

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

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

1-methylphospholane-1-oxide;

1-ethylphospholane-1-oxide;

1-n-propylphospholane-1-oxide;

1-isopropylphospholane-1-oxide;

1-n-butylphospholane-1-oxide;

1-isobutylphospholane-1-oxide;

1-2-butylphospholane-1-oxide;

Tert-butylphospholane-1-oxide;

1-n-pentylphospholane-1-oxide;

1-neo-pentylphospholane-1-oxide;

1-n-hexylphospholane-1-oxide;

1-n-heptylphospholane-1-oxide;

1-n-octylphospholane-1-oxide;

1-dimethylaminophospholane-1-oxide;

1-diethylaminophospholane-1-oxide, and / or

1-phenoxyphospholane-1-oxide.

Among the compounds of the formulas III-V, particularly preferred compounds within the scope of the invention are 1-methyl-2,3-dihydro-1H-phosphol-1-oxide (same as compound IIIa), 1-methyl-2, 5-dihydro-1H-phosphol-1-oxide (same as compound IVa) and / or 1-methyl-phospholan-1-oxide (same as compound Va), and fluorination by halogen substitution is R ¹⁶ It is carried out in one or more compounds of formula III, IV and / or V wherein methyl and R ¹⁷ to R ²⁴ are hydrogen.

In a particularly convenient manner, the new process is further modified in that the fluorination by halogen substitution is carried out in 1-alkyl-phospholane-1-oxide of formula V, and 1-methyl-phospholane-1-oxide (Same as compound Va) is particularly convenient.

The novel process applies to many of the compounds corresponding to formula (I), and these bases are also included in that they include the structure of formula (I) as aromatic subunits in larger molecules.

Within the scope of the present invention, compounds of formula VI are prepared by methods conveniently modified from compounds of formula VII:

In the above formula,

R ^{1 '} to R ^5' are the same or different and are hydrogen, F, Cl, Br, I, NO ₂ , CF ₃ , CN, CHO, COF, SO ₂ F, SO ₂ Cl, OCF ₃ , SCF ₃ , SO ₂ radicals which are ₂ CF ₃ , COOR ⁷ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ or OR ^12, or are in the ortho position with respect to each other and derived from groups R ^{1 ′} to R ^{5 ′} together are —OC -NR ¹³ -CO, R ⁷ to R ¹³ are the same as in Formula I, and when the compound of Formula VI is an aromatic mononuclear halogenated compound, at least one radical of groups R ^{1 '} to R ^5' is NO ₂ , CF ₃ , CN , CHO, COOH, COCl, COF, SO ₂ F, SO ₂ Cl, SO ₂ CF ₃ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ or COR ¹¹ , wherein the compound of formula VI is preferably three halogens on the aromatic nucleus In the case of an aromatic multinuclear halogenated compound having substituents, all remaining radicals of the groups R ^{1 '} to R ^5' may be hydrogen,

Hal is Cl or Br.

According to the invention, compounds of formula VIII are successfully prepared from the corresponding chlorinated or brominated compounds of formula IX.

In the above formula,

R ^{1 '} to R ^4' are the same or different and are hydrogen, F, Cl, Br, I, NO ₂ , CF ₃ , CN, CHO, COF, SO ₂ F, SO ₂ Cl, OCF ₃ , SCF ₃ , SO ₂ radicals which are ₂ CF ₃ , COOR ⁷ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ or OR ^12, or are in the ortho position with respect to each other and derived from groups R ^{1 ′} to R ^{4 ′} together are —OC -NR ¹³ -CO, R ⁷ to R ¹³ are the same as in formula (I), and when the compound of formula (VIII) is a heteroaromatic mononuclear halogenated compound, at least one radical of the groups R ^{1 '} to R ^4' is NO ₂ , CF ₃ , CN, CHO, COOH, COCl, COF, SO ₂ F, SO ₂ Cl, SO ₂ CF ₃ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ or COR ¹¹ , wherein the compound of formula VIII is preferably In the case of heteroaromatic multinuclear halogenated compounds having halogen substituents, all remaining radicals of groups R ^{1 ′} to R ^{4 ′} may be hydrogen,

Hal is Cl or Br.

Finally, in a particularly preferred embodiment, the novel methods can also be used to prepare compounds of formula (X), (XI) and (XII) or (XIII) from the corresponding chlorinated or brominated compounds of formula (Xa), XIa, XIIa or XIIIa.

In the above formula,

R ^{1 '} to R ^3' are the same or different and are hydrogen, F, Cl, Br, I, NO ₂ , CF ₃ , CN, CHO, COF, SO ₂ F, SO ₂ Cl, OCF ₃ , SCF ₃ , SO ₂ radicals which are ₂ CF ₃ , COOR ⁷ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ or OR ¹² , if possible, are in the ortho position relative to one another and are derived from groups R ^{1 ′} to R ^{3 ′} together -OC-NR ¹³ -CO, R ⁷ to R ¹³ are the same as in formula (I),

Hal is Cl or Br.

In particular, it goes without saying that in the case of nitrogen-containing heteroaromatic compounds, for example pyridine derivatives of formula (VIII), these fluorinated aromatic compounds which are components of macromolecular formation can be prepared successfully, May be similar.

In the above formula,

The radical R ′ has the same meanings as given for the compound of formula VIII.

Further, within the scope of the novel process of the present invention, fluorination by halogen substitution is preferably carried out at a temperature of about room temperature to a lower boiling point of the boiling point of the reaction medium and of the starting compound corresponding to the compound of formula (I). . In this context, it should be particularly stressed that the temperature can usually be kept lower than in previously known methods without loss in relation to the reaction rate.

In a preferred embodiment, the novel Halex process is typical of fluorination by halogen substitution carried out in a temperature range of about 40 ° C to about 270 ° C. In particular, in a preferred variant, the reaction temperature is in the range of about 60 ° C to about 220 ° C.

Fluorinating agents that can be used according to the invention include, in principle, alkylammonium radicals, alkylphosphonium radicals or arylphosphonium radicals in which Me is derived from alkali metals, ammonium or phosphonium or ammonium or phosphonium. Compounds such as sodium fluoride, potassium fluoride, cesium fluoride, tetramethylammonium fluoride, and other tetraalkylammonium fluorides in which the alkyl is ethyl, n-propyl or n-butyl are convenient.

Tetraphenylphosphonium fluoride is also particularly convenient. However, phosphorus fluoride is particularly preferred among the compounds of formula II (MeF) which provide fluorine and can be used successfully within the scope of the present invention because of the low cost.

Fluorinated agents are used in amounts sufficient to achieve the desired level of halogen substitution. They are preferably used stoichiometrically based on the amount of starting compound corresponding to the compound of formula (I). Furthermore, they are preferably used in molar excess, particularly preferably 1.1 to 2.0 times molar excess, based on the molar amount of halogen atoms substituted in the starting compound (s).

Where appropriate, the efficacy (especially high per se) of the reaction medium used according to the invention can be improved by the addition of compounds having a catalytic effect. In general, all catalysts known to those skilled in the art can be used for this purpose, for example catalysts from the references cited above. The catalyst which can be used in particular ^{_{(R '') 4 N +}} Hal - ( wherein, Hal is Cl or Br, R '' is C ₁ -C ₄ straight or branched-alkyl); (R ''') ₄ P ⁺ Hal ^- wherein Hal is Cl or Br and R''' is straight or branched C ₁ -C ₄ -alkyl, or aryl, preferably phenyl; Crown ethers; Polyethylene glycol and / or pyridinium salts. The process of the invention particularly relates to catalytically active amounts of tetramethylammonium chloride, tetrabutylammonium chloride, tetraphenylphosphonium chloride, 18-crown-6, PEG and / or R ²⁸ R ²⁹ Np-pyridinium-R ³⁰ , wherein R ²⁸ to R ³⁰ are preferably advantageous when using an alkyl radical having 1 to 8 carbon atoms, which may be straight or branched.

As already indicated, the workup of the reaction mixture after fluorination can be advantageously carried out by fractional distillation of the reaction mixture and the solvent can be separated and recycled. For aqueous workup, the mixture is poured into excess water and the resulting product is filtered and then extracted with an organic solvent.

In this context, the compounds of the formulas III to V can be extracted continuously, simply and completely from the reaction solution in a continuous extractor using dichloromethane or trichloromethane.

When using the process according to the invention, the desired product in question is obtained in a particularly high degree of purity. Thus, products with a purity of at least 90% of the crude product can in principle be obtained by the methods described herein. For example, it is surprising that the compounds of formulas III to V, which are virtually free of any impurities, can be extracted and a crude product having a purity of at least 95% is obtained after removing the solvent.

The present invention also relates to the reaction medium for the starting materials, diluents when the fluorinated aromatic compounds of formula (I) are prepared by reacting a compound of formula (I) wherein one of the radicals R ¹ to R ⁶ is Cl or Br with a fluoride of formula (II) Or 1-alkyl-2,3-dihydro-1H-phosphol-1-oxide of formula (III), 1-alkyl-2,5-dihydro of formula (IV) as a solvent or additive to such a medium, diluent or solvent And to the use of 1-alkyl-phospholan-1-oxide of formula (V).

Formula I

Formula II

MeF

Formula III

Formula IV

Formula V

In the above formula,

W is N or CR ³ ,

X is N or CR ⁴ ,

Y is N or CR ⁵ ,

Z is N or CR ⁶ ,

R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and hydrogen, F, Cl, Br, I, NO ₂ , CF ₃ , CN, CHO, COF, SO ₂ F, SO ₂ Cl, OCF ₃ , SCF ₃ , SO ₂ CF ₃ , COOR ⁷ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ or OR ^12, or are in the ortho position relative to one another and derived from groups R ¹ to R ⁶ The two radicals together are —OC—NR ¹³ —CO—,

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are the same or different and independently from each other hydrogen, straight or branched C ₁ to C ₆ -alkyl, aryl, preferably phenyl, Or arylalkyl, the alkyl radical and the arylalkyl radical may be substituted up to three times by halogen if appropriate, preferably CF ₃ and CHal _X H _3-X ,

Two or more of the radicals R ¹ to R ¹³ are suitably linked to one another to form one or more three to seven membered rings,

Provided that (i) W, X and Y are not N at the same time;

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

(iii) a) when the compound of formula (I) is an aromatic mononuclear halogenated compound, at least one of the remaining radicals of groups R ¹ to R ⁶ is NO ₂ , CF ₃ , CN, CHO, COOH, COCl, COF, SO ₂ F, SO ₂ Cl, SO ₂ CF ₃ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ or COR ¹¹ ;

b) when the compound of formula (I) is preferably an aromatic multinuclear halogenated compound having three halogen substituents on the aromatic nucleus, all remaining radicals of groups R ¹ to R ⁶ may be hydrogen;

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

The four radicals R ¹⁴ may be the same or different independently of one another and are hydrogen or straight or branched C ₁ to C ₈ -alkyl, wherein the alkyl radicals may for example be substituted by aromatic radicals, 4 Radicals R ¹⁵ may be independently the same or different from each other, may be the same as R ¹⁴ or be phenyl,

R ¹⁶ is straight or branched alkyl radical of 1 to 8 carbon atoms, phenyl, benzyl, cycloalkyl, OR ²⁵ or NR ²⁶ R ²⁷ , wherein R ²⁵ to R ²⁷ are the same as or different from each other independently and are linear or branched Is an alkyl radical having 1 to 4 carbon atoms),

R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ are independently the same or different from each other and are hydrogen, phenyl or straight or branched C _1-8 -alkyl radicals.

In this context, particular preference is given to using compounds of the formulas III to V in the reaction medium as well as the reaction medium itself without the addition of any further diluents or solvents.

The following examples are used to illustrate the subject matter of the present invention.

Examples 1-14 and Comparative Examples 1-12a

1.0 mol of organic base in 50 ml of solvent is initially introduced into a three necked flask equipped with a thermometer and bubble counter, and 0.12 to 0.2 mol of potassium fluoride KF (for each chlorine atom) is added in the absence of moisture (N ₂ ). The reaction mixture is heated at a certain temperature for a certain time (see Table 1 below). Samples are occasionally taken from the reaction mixture and used to monitor the conversion level by reaction progress and gas chromatography. The reaction mixture is worked up until the starting compound is no longer detected.

During workup, the reaction mixture is poured into excess water, the solid components are filtered off and, if appropriate, extracted with CH ₂ Cl ₂ to separate the liquid product, washed with water and dried. The resulting mixture can be analyzed by GC, GCMS and ¹⁹ F NMR. The product is further purified by recrystallization from a suitable solvent or fractional distillation under atmospheric or reduced pressure.

Table 1 below provides an overview of the base used in the examples, the reaction medium used for fluorination by halogen substitution, other reaction conditions, conversion levels and total product yield.

Experiment number Starting compound / product menstruum Time [h] T [℃] transform[%] yield(%) Comparative Example 1 4-nitrochlorobenzene / 4-nitrofluorobenzene TMS 5 170 6 Comparative Example 1a ^* 4-nitrochlorobenzene / 4-nitrofluorobenzene TMS 8 235-240 82 Comparative Example 1b ^* 4-nitrochlorobenzene / 4-nitrofluorobenzene TMS 5 180 85 Comparative Example 2 4-nitrochlorobenzene / 4-nitrofluorobenzene NMP 5 170 19 Comparative Example 3 4-nitrochlorobenzene / 4-nitrofluorobenzene DMSO 5 170 61 Example 1 4-nitrochlorobenzene / 4-nitrofluorobenzene 1 ^* ) 5 170 85 Example 2 4-nitrochlorobenzene / 4-nitrofluorobenzene 2 ^* ) 4.5 170 86 Example 3 4-nitrochlorobenzene / 4-nitrofluorobenzene 3 ^* ) 3.5 165 100 96 Comparative Example 4 2-nitrochlorobenzene / 2-nitrofluorobenzene DMSO 5 170 42 Example 4 2-nitrochlorobenzene / 2-nitrofluorobenzene 3 ^* ) 5 170 82 Comparative Example 5 2-nitrochlorobenzene / 2-nitrofluorobenzene DMSO 6.5 170 64 Comparative Example 5a ^* 2-nitrochlorobenzene / 2-nitrofluorobenzene Phthal-dichlor 10 210 85 87 Example 5 2-nitrochlorobenzene / 2-nitrofluorobenzene 3 ^* ) 4.5 170 99 79 Comparative Example 6 2,4-dinitrochlorobenzene / 2,4-dinitrofluorobenzene DMSO 3 60 72 Comparative Example 7 2,4-dinitrochlorobenzene / 2,4-dinitrofluorobenzene CH ₃ CN 3 60 8 Example 6 2,4-dinitrochlorobenzene / 2,4-dinitrofluorobenzene 3 ^* ) 3 60 76 Comparative Example 8 2,4-dinitrochlorobenzene / 2,4-dinitrofluorobenzene DMSO 5 60 95 81 Example 7 2,4-dinitrochlorobenzene / 2,4-dinitrofluorobenzene 3 ^* ) 5 60 100 87 Comparative Example 9 2-fluoro-3,5-dichloropyridine / 2,3-difluoro-5-chloropyridine DMSO 5 160 5

Experiment number Starting compound / product menstruum Time [h] T [℃] transform[%] yield(%) Example 8 2-fluoro-3,5-dichloropyridine / 2,3-difluoro-5-chloropyridine 3 ^* ) 5 160 45 Comparative Example 10 2-fluoro-3,5-dichloropyridine / 2,3-difluoro-5-chloropyridine DMSO 13 160 24 Example 9 2-fluoro-3,5-dichloropyridine / 2,3-difluoro-5-chloropyridine 3 ^* ) 8 160 61 55 Comparative Example 11 2,4-dichloronitrobenzene / 2,4-difluoronitrobenzene DMSO 1.5 140 69 Comparative Example 11a ^* 2,4-dichloronitrobenzene / 2,4-difluoronitrobenzene Pyridyl-nitrile 6 170-180 73 Example 10 2,4-dichloronitrobenzene / 2,4-difluoronitrobenzene 3 ^* ) 1.5 140 100 86 Example 11 1,3,5-trichlorobenzene / 1,3-dichloro-5-fluorobenzene, 1,3-difluorochlorobenzene 3 ^* ) 8 210 6040 } 88 Example 12 3,4-dichloro-benzene fluoride / 3-chloro-4-fluorobenzene fluoride 3 ^* ) 14 210 95 78 Comparative Example 12a ^* 2,4-dichlorobenzaldehyde / 2,4-difluorobenzaldehyde TMS 15 210-220 68 Example 13 2,4-dichlorobenzaldehyde / 2,4-difluorobenzaldehyde 3 ^* ) 8 190 99 71 Example 14 2,5-dichloro-4-aminopyridine / 2-fluoro-5-chloro-4-aminopyridine 3 ^* ) 6 150 100 76 1 ^* ) = 1-methyl-2,3-dihydro-1H-phosphol-1-oxide = compound of formula IIIa 2 ^* ) = 1-methyl-2,5-dihydro-1H-phosphol-1- Oxide = compound of formula IVa 3 ^* ) = 1-methylphospholane-1-oxide = compound of formula Va Comparative Example 1a ^* = Comparative Example Derived from D11 Comparative Example 1b ^* = Tetraphenylphosphonium as catalyst Comparative Example Derived from D15 Added Comparative Example 5a ^* = Comparative Example Derived from D12 Comparative Example 11a ^* = Comparative Example Derived from D13 Added Tetraphenylphosphonium as Catalyst Comparative Example 12a ^* = Comparative Example Derived from D14

Example 15

Process for preparing 2,4,6-trifluoropyrimidine by reaction of 2,4,6-trichloropyrimidine in the presence of 1-methyl-2,3-dihydro-1H-phosphol-1-oxide

183 g (1 mol) of 2,4,6-trichloropyrimidine, 228 g (4 mol) of KF and 20 g (0.17 mol) of 1-methyl-2,3-dihydro-1H-phospho-1-oxide and 400 ml of sulfolane It is initially introduced into a 1.5 L four-necked flask equipped with a reflux condenser with thermometer, stirrer and bubble counter. The mixture is then heated at 100 ° C. for 3 hours with stirring. After completion of the reaction, the product (2,4,6-trifluoropyrimidine) is distilled off in a vessel flask under reduced pressure and purified continuously by distillation. Conversion: 100%, yield: 127 g (95% of theory).

Comparative Example 13

Method for preparing 2,4,6-trifluoropyrimidine by reaction of KF and 2,4,6-trichloropyrimidine 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 reaction is carried out as described in Example 15. The conversion (based on 2,4,6-trifluoropyrimidine) is 42% (yield 35%).

Further advantages and aspects of the invention emerge from the following claims.

Claims (12)

1-alkyl-2,3-dihydro-1H-phosphol-1-oxide of formula III, 1-alkyl-2,5-dihydro-1H-phosphol-1-oxide of formula IV and / or In a reaction medium comprising 1-alkyl-phospholan-1-oxide of V, a compound of formula I wherein one of the radicals R ¹ to R ⁶ is Cl or Br is fluorinated by halogen substitution by reacting with a fluoride of formula II A process for preparing a fluorinated aromatic compound of formula I, characterized in that Formula I Formula II MeF Formula III Formula IV Formula V In the above formula, W is N or CR ³ , X is N or CR ⁴ , Y is N or CR ⁵ , Z is N or CR ⁶ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and hydrogen, F, Cl, Br, I, NO ₂ , CF ₃ , CN, CHO, COF, SO ₂ F, SO ₂ Cl, OCF ₃ , SCF ₃ , SO ₂ CF ₃ , COOR ⁷ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ or OR ^12, or are in the ortho position relative to one another and derived from groups R ¹ to R ⁶ The two radicals together are —OC—NR ¹³ —CO—, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are the same or different and independently from each other hydrogen, straight or branched C ₁ to C ₆ -alkyl, aryl, preferably phenyl, Or arylalkyl, the alkyl radical and the arylalkyl radical may be substituted up to three times by halogen if appropriate, preferably CF ₃ and CHal _X H _3-X , Two or more of the radicals R ¹ to R ¹³ are suitably linked to one another to form one or more three to seven membered rings, Provided that (i) W, X and Y are not N at the same time; (ii) at least one of the radicals R ¹ to R ⁶ must be fluorine; (iii) a) when the compound of formula (I) is an aromatic mononuclear halogenated compound, at least one of the remaining radicals of groups R ¹ to R ⁶ is NO ₂ , CF ₃ , CN, CHO, COOH, COCl, COF, SO ₂ F, SO ₂ Cl, SO ₂ CF ₃ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ or COR ¹¹ ; b) when the compound of formula (I) is preferably an aromatic multinuclear halogenated compound having three halogen substituents on the aromatic nucleus, all remaining radicals of groups R ¹ to R ⁶ may be hydrogen; Me is Na, K, Cs, Rb, N (R ¹⁴ ) ₄ or P (R ¹⁵ ) ₄ , The four radicals R ¹⁴ may be the same or different independently of one another and are hydrogen or straight or branched C ₁ to C ₈ -alkyl, wherein the alkyl radicals may for example be substituted by aromatic radicals, 4 Radicals R ¹⁵ may be independently the same or different from each other, may be the same as R ¹⁴ or be phenyl, R ¹⁶ is straight or branched alkyl radical of 1 to 8 carbon atoms, phenyl, benzyl, cycloalkyl, OR ²⁵ or NR ²⁶ R ²⁷ , wherein R ²⁵ to R ²⁷ are the same as or different from each other independently and are linear or branched Is an alkyl radical having 1 to 4 carbon atoms), R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ are independently the same or different from each other and are hydrogen, phenyl or straight or branched C _1-8 -alkyl radicals. The process of claim 1, wherein the fluorination by halogen substitution is carried out as reaction medium 1-alkyl-2,3-dihydro-1H-phosphol-1-oxide of formula III, 1-alkyl-2,5-di of formula IV. The process is carried out in hydro-1H-phosphol-1-oxide and / or 1-alkyl-phospholan-1-oxide of formula (V). The process according to claim 1 or 2, wherein the fluorination by halogen substitution is carried out in 1-alkylphospholane-1-oxide of formula (V). The process according to claim 1, wherein the fluorination by halogen substitution is carried out in at least one compound of formula III, IV and / or V wherein R ¹⁶ is methyl and R ¹⁷ to R ²⁴ are hydrogen. 5. The process of claim 1, wherein the compound of formula VI is prepared from the corresponding chlorinated or brominated compound. 6. Formula VI In the above formula, R ^{1 '} to R ^5' are the same or different and are hydrogen, F, Cl, Br, I, NO ₂ , CF ₃ , CN, CHO, COF, SO ₂ F, SO ₂ Cl, OCF ₃ , SCF ₃ , SO ₂ radicals which are ₂ CF ₃ , COOR ⁷ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ or OR ^12, or are in the ortho position with respect to each other and derived from groups R ^{1 ′} to R ^{5 ′} together are —OC -NR ¹³ -CO, R ⁷ to R ¹³ are the same as defined in claim 1, and when the compound of formula VI is an aromatic mononuclear halogenated compound, at least one radical of the groups R ^{1 '} to R ^5' is NO ₂ , CF ₃ , CN, CHO, COOH, COCl, COF, SO ₂ F, SO ₂ Cl, SO ₂ CF ₃ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ or COR ¹¹ , wherein the compound of formula VI is preferably an aromatic nuclear phase In the case of an aromatic multinuclear halogenated compound having three halogen substituents in the group, all remaining radicals of the groups R ^{1 '} to R ^5' may be hydrogen. 5. The process according to claim 1, wherein the compound of formula VIII is prepared from the corresponding chlorinated or brominated compound. 6. Formula VIII In the above formula, R ^{1 '} to R ^4' are the same or different and are hydrogen, F, Cl, Br, I, NO ₂ , CF ₃ , CN, CHO, COF, SO ₂ F, SO ₂ Cl, OCF ₃ , SCF ₃ , SO ₂ radicals which are ₂ CF ₃ , COOR ⁷ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ or OR ^12, or are in the ortho position with respect to each other and derived from groups R ^{1 ′} to R ^{4 ′} together are —OC Or —NR ¹³ —CO, R ⁷ to R ¹³ are as defined in claim 1 and when the compound of formula VIII is a heteroaromatic mononuclear halogenated compound, at least one radical of groups R ^{1 ′} to R ^{4 ′} is NO ₂ , CF ₃ , CN, CHO, COOH, COCl, COF, SO ₂ F, SO ₂ Cl, SO ₂ CF ₃ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ or COR ¹¹ , the compound of formula VIII is preferably aromatic In the case of heteroaromatic multinuclear halogenated compounds having three halogen substituents on the nucleus, the remaining radicals of the groups R ^{1 '} to R ^4' may all be hydrogen. 5. The process according to claim 1, wherein the compound of formula X, XI and XII or XIII is prepared from the corresponding chlorinated or brominated compound. 6. Formula X Formula XI Formula XII Formula XIII In the above formula, R ^{1 '} to R ^3' are the same or different and are hydrogen, F, Cl, Br, I, NO ₂ , CF ₃ , CN, CHO, COF, SO ₂ F, SO ₂ Cl, OCF ₃ , SCF ₃ , SO ₂ radicals which are ₂ CF ₃ , COOR ⁷ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ or OR ¹² , if possible, are in the ortho position relative to one another and are derived from groups R ^{1 ′} to R ^{3 ′} together -OC-NR ¹³ -CO, and R ⁷ to R ¹³ are the same as defined in claim 1. The process according to claim 1, wherein the fluorination by halogen substitution is carried out at a temperature of about room temperature to a lower boiling point of the boiling point of the reaction medium and of the starting compound corresponding to the compound of formula (I). . The method of claim 8, wherein the fluorination by halogen substitution is carried out in a temperature range of about 40 ° C. to about 270 ° C. 10. The amount of one or more compounds of the compounds of Formulas III to V in an amount of 1.0 to 100 mol% according to claim 1, wherein the reaction medium is based on the compound of formula I wherein one of the radicals R ¹ to R ⁶ is Cl or Br. How to include. When a fluorinated aromatic compound of formula I is prepared by reacting a compound of formula I wherein one of the radicals R ¹ to R ⁶ is Cl or Br with a fluoride of formula II, the reaction medium, diluent or solvent for the starting material, or such 1-alkyl-2,3-dihydro-1H-phosphol-1-oxide of formula III, 1-alkyl-2,5-dihydro-1H-phosphol of formula IV as an additive to a medium, diluent or solvent Use of -1-oxides and / or 1-alkyl-phospholan-1-oxides of formula V. Formula I Formula II MeF Formula III Formula IV Formula V In the above formula, W is N or CR ³ , X is N or CR ⁴ , Y is N or CR ⁵ , Z is N or CR ⁶ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and hydrogen, F, Cl, Br, I, NO ₂ , CF ₃ , CN, CHO, COF, SO ₂ F, SO ₂ Cl, OCF ₃ , SCF ₃ , SO ₂ CF ₃ , COOR ⁷ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ or OR ^12, or are in the ortho position relative to one another and derived from groups R ¹ to R ⁶ The two radicals together are —OC—NR ¹³ —CO—, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are the same or different and independently from each other hydrogen, straight or branched C ₁ to C ₆ -alkyl, aryl, preferably phenyl, Or arylalkyl, the alkyl radical and the arylalkyl radical may be substituted up to three times by halogen if appropriate, preferably CF ₃ and CHal _X H _3-X , Two or more of the radicals R ¹ to R ¹³ are suitably linked to one another to form one or more three to seven membered rings, Provided that (i) W, X and Y are not N at the same time; (ii) at least one of the radicals R ¹ to R ⁶ must be fluorine; (iii) a) when the compound of formula (I) is an aromatic mononuclear halogenated compound, at least one of the remaining radicals of groups R ¹ to R ⁶ is NO ₂ , CF ₃ , CN, CHO, COOH, COCl, COF, SO ₂ F, SO ₂ Cl, SO ₂ CF ₃ , CONR ⁸ R ⁹ , SO ₂ R ¹⁰ or COR ¹¹ ; b) when the compound of formula (I) is preferably an aromatic multinuclear halogenated compound having three halogen substituents on the aromatic nucleus, all remaining radicals of groups R ¹ to R ⁶ may be hydrogen; Me is Na, K, Cs, Rb, N (R ¹⁴ ) ₄ or P (R ¹⁵ ) ₄ , 4 radicals R¹⁴May be the same or different independently from each other, and hydrogen or C of straight or branched chain_OneTo C₈-Alkyl, wherein the alkyl radical may for example be substituted by an aromatic radical, and four radicals R¹⁵May be the same or different independently of each other, and R¹⁴Wow May be the same or phenyl, R ¹⁶ is straight or branched alkyl radical of 1 to 8 carbon atoms, phenyl, benzyl, cycloalkyl, OR ²⁵ or NR ²⁶ R ²⁷ , wherein R ²⁵ to R ²⁷ are the same as or different from each other independently and are linear or branched Is an alkyl radical having 1 to 4 carbon atoms), R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ are independently the same or different from each other and are hydrogen, phenyl or straight or branched C _1-8 -alkyl radicals. Use according to claim 11, wherein the compounds of the formulas III to V are used as the reaction medium.