CA2090768A1

CA2090768A1 - Process for the preparation of 2,4,5-trifluorobenzonitrile

Info

Publication number: CA2090768A1
Application number: CA002090768A
Authority: CA
Inventors: Ralf Pfirmann; Theodor Papenfuhs
Original assignee: Individual
Current assignee: Clariant Produkte Deutschland GmbH
Priority date: 1992-02-26
Filing date: 1993-02-25
Publication date: 1993-08-27
Also published as: EP0557949A2; ES2125919T3; DE59309216D1; EP0557949A3; JPH069535A; EP0557949B1

Abstract

Abstract of the disclosure:

Process for the preparation of 2,4,5-trifluorobenzo-nitrile The present invention relates to a process for the preparation of 2,4,5-trifluorobenzonitrile in which 2,4-dichloro-5-fluorobenzonitrile is reacted with approxi-mately 100 to approximately 300 mol % of an alkali metal fluoride or of a tetraalkyl(C1-C18)ammonium fluoride or mixtures of such fluorides per chlorine atom to be exchanged, at temperatures from approximately 80 to approximately 250°C, in the presence of a phase transfer catalyst, if appropriate in a dipolar aprotic solvent.

Description

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HOECHST AXTIENGESELLSCHAFT - HOE 92/F 051 Dr.BI/St Description Procass for the preparation of 2,4,5-trifluorobenzo-nitrile The present invention relates to a no~el, Lmproved pro-cess for the preparation nf 2,4,5-trifluorobenzonitrile, a valuable intermediate for the preparation of antibac-terial agents from the fluoroquinolonecarboxylic acid series via the hydrolysis product 2,4,5-trifluorobenzoic acid.

To date, it was only possible to prepare 2,4,5-trifluoro-benzonitrile, which can be converted by methods known from the literature tEP 431 373, EP 433 124, H. Henecka in Houben-Weyl-Muller, Methoden dex Organischen Chemie [Methods of Organic Chemistry], Vol. 8 (1952), 427-433) first into 2,4,5-trifluorobenzoic acid and then into the active substances (J.P. Sanchez et al., J. Med. Chem. 31 (1988), 983-991; EP 227 088; DE 3 600 891; DE 3 420 743;
JP 60 072 885; EP 191 185), by economically unfavorable processes which are unsatisfactory from the industrial point of view.

Halex (chlorine/fluorine exchange) reaction of 2,4-dichloro-5-fluorobenzonitrile (EP 431 373) in the solvent dimethyl sulfoxide, which is undesirable from the indus-trial point of view, with the use of spray-dried potas-sium fluoride gives poor yields (43 ~) of 2,4,5-tri-fluorobenzonitrile. Furthermore, 2,4,5-trifluoro-benzonitrile is obtained as a by-product in yields of approximately 20 % in the preparation of 2-chloro-4,5-difluorobenzonitrile (EP 433 124) or by bromine/cyano exchange of 2,4,5-trifluorobromobenzene by means of alkali metal cyanides (EP 191 195).

2,4,5-Trifluorobenzoic acid can also be prepared ~ia other routes, but some of these are unfavorable because ~- ~

they comprise several steps and entail poor total yields, others because of their problems due to the materials and reactions which are involved. These routes include the fluorination of 2,5-difluoro-4-chlorobenzoyl fluoride (PCT WO 90/12 780) and 2,4-dichloro-5-fluorobenzoyl fluoride (JP 01/226 851; DE 3 420 7~6; EP 164 619) to gi~e 2,4,5-trifluorobenzoyl fluoride, followed by hydro-lysis. They also include the traditional fluorination of 4,5-difluoroanthranilic acid by the Schiemann reaction to give 2,4,5-trifluorobenzoic acid (G.C. Finger et al., CA 50 (1955), 9312). Problems due to materials can be found in dehalogenation reac~ions of tetrafluorophthalo-dinitriles (EP 307 897, JP 01/160 944) or tetrafluoro-ph~halate diesters. All these methods have a selective decarboxylation of the resulting trifluoro(iso)phthalic acids in common, frequently resulting in substantial isomer residues which are difficult to remove (US 4 935 541, JP 01/052 737; JP 01/025 737). Equally, it is impossible to obtain 2,4,5-trifluorobenzoic acid by complete selective decarboxylation of trifluorophthalic acid obtained by fluorination of 3,4,6-trichlorophthalim-ides (EP 431 294) followed by hydrolysis.

The acylation of 1,2,4-trifluorobenzene by means of acetyl chlorides which are optionally chlorinated in the aliphatic moiety followed by haloform reaction (EP 411 252, DE 3 840 371, DE 3 840 375, JP 02 184 650) is unfavorable from the economic point of view since 1,2,4-trifluorobenzene itself must be prepared, which involves complicated steps as they are typical for the Schiemann reaction.

It has now been found that 2,4,5-trifluorobenzonitrile can be prepared in good yields by a novel, improved process, in which 2,4-dichloro-5-fluorobenzonitrile is reacted with approximately 100 to approximately 300 mol %, pref~rably approximately 105 to approximately 150 mol %, particularly preferably approximately 110 to .. ' 3~7~

approximately 120 mol %, of an alkali me~al fluoride ox of a ~etraalkyl(Cl-Cla)ammonium fluoride per chlorine atom to be exchanged, at temperatures from approximately 80 to approximately 250C, preferably from approximately 140 to approximately 200C, particularly preferably from approximately 160 to approximately 190C, in the presence of a phase transfer catalyst, if appropriate in a dipolar aprotic solvent.

Suitable alkali metal fluorides are mainly potassium fluoride, rubidium fluorlde and cesium fluoride, in exceptional cases also lithium fluoride or sodium fluor-ide. Potassium 1uoride, rubidium fluoride or cesium fluoride, or mixtures of these, are pre~erably employed.
Mixtures o~ potassium fluoride and cesium fluoride are preferred. Particularly preferred mixtures are those which contain approximately 10 % by weight of cesium fluoride.

It is also possible ~o employ spray-dried alkali metal fluoride~ in the process according to the invention.

Suitable phase transfer catalysts are quaternary ammonium or phosphonium compounds, such as tetraalkyl(Cl-Cl~)ammon-ium chlorides, tetraalkyl(C1-C18)ammonium bromides or tetraalkyl(Cl-Cl8)ammonium fluorides, tetraalkyl(Cl-Cl8)-phosphonium chlorides or tetraalkyl(C1-C18)phosphonium bromides, tetraphenylphosphonium chloride or tetraphenyl-phosphonium bromide or (phenyl)m(alkyl(cl-cl8))n phosphon-ium chlorides or (phenyl)~(alkyl(C1-C18))n-phosphonium bromides, where m is 1 to 3, n is 3 to 1 and m+n is 4.
Preferred from amongst these are phosphonium salts, particularly preferably tetraalkyl(C1-C18)phosphonium bromides. These substances are employed in amounts of approximately 0.01 to approximately 50 mol %, preferably of approximately 0.5 to approximately 10 mol %, particu-larly preferably of approximately 1 to approximately 5 mol %, based on 2,4-dichloro-5-fluorobenzonitrile. If - 4 ~
a tetraalkyl(Cl-Cl~)ammonium fluoride is used as fluoride salt, then the addition of other phase transfer catalysts can be dispensed with since the fluoride salt itself represents such a catalyst.

Oligo- or polyethylene glycol dimethyl ethers can also be employed as phase transfer catalysks. The number of glycol units in these compounds can be from approximate-ly 4 (tetraethylene glycol dimethyl ether) to approxi-mately 150; however, preferred polyethylene glycol dimethyl ethers which are employed are those whose degree of polymerization is between approximately 4 and approxi-mately 25. The optLmum amount of these glycol ethers to be employed is between approximately 0.5 % by weight and approximately 200 % by weight, relative to the fluoride employed. The glycol ethers are preferably used in amounts of between approximately 5 and approximately 100 % by weight, particularly preferably between approxi-mately 10 and approximately 50 % by weight, relative to the fluoride employed. The particular advantage of the use of these compounds is that, as a rule, less solvent can be used relative to the amount of compounds employed because the glycol ethers are always liquid at the reaction temperature.

Surprisingly, the use of phase transfer catalysts allows a virtually quantitative reaction, while without such an addition reaction rates of more than 70 % can scarcely be observed, but instead rapidly increasing decomposition rates.

The process according to the invention can be carried out in the complete absence of a solvent. However, it is also possible to carry out the reaction in a dipolar aprotic solvent, for example in sulfolane (tetramethylene sul-fone), tetramethylene sulfoxide, N,N-diethylacetamide, N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-pyrrolidone, dimethyl sulfoxide, dimethyl sulfone, 5 2B~7~

diphenyl sulfoxide, diphenyl sulfone, tetramethylurea,tetra-n-butylurea, 1,3-dimethylLmidazolidin-2 one, or in mixtures of these.

In general, the product mixture obtained by the process according to the invention is obtained by fil~ering the reaction salt and/ in particular when carried out on an industrial scale, subsequent removal of the volatile components by distillation and fractionation. Direct fractionation of the filtrate is also possible. It is equally possible to treat the crude mixture with water and to remove the lighter top phase, which contains the product. Extraction of the water allows complete separa-tion of the product from the mother liquor. This can be followed by purification by means of chromatography or separation by distillation.

The process can be carried out under atmospheric pres-sure, subatmospheric or superatmospheric pressure. It is preferred to carry out the process under a slight super-atmospheric pressure in a sealed vessel so as to avoid loss of the volatile product, since the vapor pressure of the latter at the reaction temperatures is already considerable. This effect can be utilized for distilling off the product continuously during the reaction, but this requires a more complicated apparatus and control ~5 technology (uniform r0flux). In general, however, a subsequent fine fractionation is still required. If optimal reaction conditions are selected, such as catalyst, concentration, temperature and amount of salt, however, this additional process step is not reguired for obtaining high yields and space-time yields.

An advantage of the process is a highly concentrated reaction solution, which is required on an industrial scale for reasons of economy. Moreover, the procedure according to the invention allows very high reaction rates to be achievedl which also results in high space-~, . ",; , v~

time yields, while the total yields still remain high ~overy high and are considerably improved compared with the processes which have already been described. At ~he same time, the process according to the invention has 5 advantages in terms of manipulation, since the use of spray-dried salt is not necessarily required. The yields are approximately 65 to approximately 85 % of theory, depending on the choice of catalyst, reaction temperature and concentration in the solvent.

10 The 2,4-dichloro-5-fluorobenzonitrile, which is employed in the process according to the invention as starting material, can be prepared from 2,4-dichloro-5-fluoro-bromobenzene by processes known from the literature by bromine/cyano exchange (EP 433 124), from 2,4-dichloro-15 5-fluoroaniline by means of cyano Sandmeyer reaction (CN 1 031 074) or from 2,4-dichloro-5-fluorobenzotri-chloride (EP 431 373) by al[monolysis.

The examples which follow illustrate the process accord-ing to the invention without restricting it thereto.

20 Use examples In some examples, the course of the reaction was moni-tored by gas chromatography by means of calibration with the aid of an internal standard (inert under the reaction conditions). This allows the amount of product formed, 25 which may be obtained by working-up as described in the text of the description, which had been dispensed with in these examples, to be determined exactly at any given points in time. These batches may be carried out on a larger scale ollowed by working-up (preferably fraction-30 ation, but also extraction or chromatography), withoutproblems and without an addition of the internal stand-ard, and in general even better results, such as shorter reaction times, higher space-time yields and better yields, are obtained by improving the stirring _ 7 _~
conditions.

Boiling point 2,4,5-trifluorobenzonitrile 100 to~r/118~
torr/102C
26 torr/78~C
15 torr/72C

Example 1 13.6 g (0.22 mol) of potassium fluoridefcesium fluoride (9:1) and 1.4 g of tetrabutylphosphonium bromide are introduced into 50 g of sulfolane. After this, approxi-mately 10 g of the solvent are distilled off in vacuo (3 mbar/140C). 19.0 g (0.1 mol) of 2,4-dichloro-S-fluorobenzonitrile are then added at 140C, and the mixture is heated for 11 hours at 190C, with vigorous stirring. 13.2 g ~84 %, 0.083g mol) of 2,4,5-trifluoro-benzonitrile can subsequently be detected in the reaction mixture by GC and can be removed from the mixture in vacuo and then fractionated.

Example 2 11.3 g (0.103 mol) of rubidium fluoride and 1.7 g of tetraoctylphosphonium bromide (3 mol %, 3 mmol) are introduced into 20 g of N-methylpyrrolidone (NMP) with stirring, and 13.6 g (0.1 mol) of 2,4-dichloro-5-fluoro-benzonitrile are added to the resulting suspension at 100C. In an autoclave, the mixture is heated for 14 hours at 210C, after which it is analyzed by gas chromatography. Calibration against the internal standard allows lû.9 g (69 %, 0.0692 mol) of 2,4,5-trifluorobenzo-nitrile to be detected.

Example 3 A reaction mixture of 95.0 g (0.5 mol) of 2~4-dichloro-5-fluorobenzonitrile, 92.9 g (1.5 mol) of potassium fluoride/cesium fluoride (9:1) and 20.3 g (8 mol ~6, 40 mmol) of hexadecyltributylphosphonium bromide is dried : , . ' ., 2~7~ ~' by incipient distillation with 40 g of toluene. After the toluene has been removed completely, the mixture is heated to 210C in a sealed apparatus (15 hours)~ The reaction salt which has been filtered off is freed from adhering product by washing with sulfolane. When the reaction has ended, 52.2 g (66 ~, 0.332 mol) of 2,4,5-trifluorobenzonitrile (degree of purity (GC): ~ 99.5 %) are isolated from the reaction mixture by frac~iona~ion.

Example 4 136.2 g (2.2 mol) of potassium fluoride/cesium fluoride (9:1) are treated with 6.0 g (1.5 mol %, 15 mmol) of n-butyltriphenylphosphonium bromide and 300 g of sulfolane.
The mixture is subjected to incipient distillation, 190.0 g (1 mol) of 2,4-dichloro-5-fluorobenzonitrile are subsequently added, and the mixture is heated at 200C.
After 9 hours, the reaction has ended. The reaction salt is removed by filtration, and the mother liquor is fractionated. This gives 118.8 g (0.756 mol, 76 ~) of 2,4,5-trifluorobenzonitrile, which distils over at 26 torr ~3.4 kPa)/78C. Small amounts of incompletely reacted benzonitriles (intermediate cuts, boiling points 80-130C/3.4 kPa) are recycled together with the redis-tilled solvent.

Example 5 Approximately 20 g of the solvent are removed from a suspension of 38.3 g (0.618 mol) of potassium fluoride/cesium fluoride (9:1) and 1.3 g (1 mol %;
3 mmol) of tetraphenylphosphonium bromide in 180 g of N,N-dimethylacetamide by distillation. The mixture is treated with 57.0 g (0.3 mol) of 2,4-dichloro-5-fluoro-benzonitrile and heated in a glass autoclave for 8 hours at 175~C, with vigorous stirring. After this, 33.7 g (71 ~, 0.214 mol) of 2,4,5-trifluorobenzonitrile can be detected in the reaction mixture by calibration against the internal standard.

2~7~j g Example 6 52.0 g (0.84 mol) of potassium fluoride/cesium fluoride (9:1) are introduced into 40 g of sulfolane, and 7.0 g of octadecyltrimethylammonium chloride (5 mol %, 20 mmol) are added. 2,4-Dichloro 5-fluorobenzonitrile (76.0 g, 0.4 mol) is added at 100C, and the reaction i5 conducted for 5 hours at 205C. After this~ 41.4 g (66 %, 0.263 mol) of 2,4,5-trifluorobenzonitrile can be d~tected by cali-bration against the internal standard.

Example 7 30 ml of anhydrous N,N-dimethylacetamide and l9.0 g (0.1 mol) of 2,4-dichloro-5-fluorobenzonitrile are added to 23.3 g (O.25 mol) of tetramethylammonium fluoride which has been dried in vacuo ~nd which is in the form of a colorless oil. ~he reaction mi~ture is kept under argon for 20 hours at 80C and then analyzed by GC. Calibration against the internal standard indicates 12.6 g (80 %, 0.0803 mol) of 2,4,5-trifluorobenzonitrile in the pale brown solution.

Example 8 Approximately 70 g of DMAc are distilled off from a suspension of 100 g of N,N-dimethylacetamide (DMAc), 50 g of polyethylene glycol dimethyl ether (n = 1000) and 38.7 g (0.625 mol) of potassium fluoride/cesium fluoride (9:1), 47.5 g (0.25 mol) of 2,4-dichloro-5-fluoro-benzonitrile are added, and the mixture is heated in a glass autoclave for 10 hours at 200C, with vigorous stirring. After this, the volatile components (product, DMAc, secondary products) are distilled off from the reaction mixture (30 torr/50C-130C), and the crude mixture is subjected to fine fractionation. After the solvent, 30.1 (28.3) g (72 %, 0.180 mol) of 2,4,5-tri-fluorobenzonitrile (degree of purity (GC) : approximately 94 %) are obtained at 85 torr/102C. A purer product is obtained when the batch size is increased.

-2 ~ 7 ~ $

Example 9 19.4 g (C.3 mol) of potassium fluoxide/cesium fluoride(5:1) are added to 50 g of sulfolane, and approximately 20-25 g of solvent are di~illed off in vacuo. 7.9 g of anhydrous te~raethylene glycol dime hyl ether and 19.0 g (0.1 mol) of 2,4-dichloro-5-fluorobenzonitrile are added to the bottom product, and the mixture is heated for 15 hours at 160C. Analysis by gas chromatography (calibration against the internal standard) subsequently demonstrates that ~he viscous reaction mixture contains 10.1 g (64 %, 0.0643 mol) of product.

Example 10 (Comparison Example) 13.6 g (0.22 mol) of potassium fluoride/cesium fluoride (9:1) are suspended in 60 g of sulfolane, and 10 g of the solvent are distilled off in vacuo. After 19.0 g (0.1 mol) of 2,4-dichloro-5-fluorobenzonitrile have been added, the mixture is heated for 20 hours at 200C. The yields of 2,4,5-trifluorobenzonitrile which have been determined by calibration against the internal standard (GC) reach a maximum of approximately 50 % of theory after 14-16 hours (in the further course of the reaction, the yields decrease again). After the reaction time, the reaction rate is approximately 85-90 %.

Example 11 (Hydrolysis Example) ~0 g (0.127 mol) of 2,4,5-trifluorobenzonitrile are added dropwise at 180C in the course of 1 hour to 30 g of 75 percent sulfuric acid. The solution, which has a temperature of 100C, is poured onto 50 g of ice, and the mixture is subjected to filtration with suction at 0C.
The product is washed three times using 30 g of ice-water and dried in vacuo at 50C. Extraction of the mother liquors with dichloromethane, drying over magnesium sulfate and removal of the solvent give 1.9 g (9 %, 0.011 mol) of pale yellowish crystals. The bulk is 19.3 g of 2,4,5-trifluorobenzoic acid (86 %, 0.110 mol) in the form of colorless crystals. The total yield is 95 %

(degree of purity (GC, HPL~) > 99 %; m~p. 98.3-99.5C)o Recrystallization from water allows product of a melting range of 100.6-101.8C to be obtained.

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Claims

1. A process for the preparation of 2,4,5-trifluoro-benzonitrile, which comprises reacting 2,4-dichloro-5-fluorobenzonitrile with approximately 100 to approximately 300 mol % of an alkali metal fluoride or of a tetraalkyl(C1-C18)ammonium fluoride or mixtures of such fluorides per chlorine atom to be exchanged, at temperatures from approximately 80 to approximately 250°C, in the presence of a phase transfer catalyst, if appropriate in a dipolar aprotic solvent.

2. The process as claimed in claim 1, wherein the reac-tion is carried out with approximately 105 to approximately 150 mol % of an alkali metal fluoride or tetraalkyl(C1-C18)ammonium fluoride or mixtures of such fluorides.

3. The process as claimed in at least one of claims 1 and 2, wherein the reaction is carried out with approximately 110 to approximately 120 mol % of an alkali metal fluoride or tetraalkyl(C1-C18)ammonium fluoride or mixtures of such fluorides.

4. The process as claimed in at least one of claims 1 to 3, wherein the reaction is carried out at temperatures from approximately 140 to approximately 200°C.

5. The process as claimed in at least one of claims 1 to 4, wherein the reaction is carried out at temperatures from approximately 160 to approximately 190 °C.

6. The process as claimed in at least one of claims 1 to 5, wherein potassium fluoride, rubidium fluoride or cesium fluoride or mixtures of these are employed as alkali metal fluorides.

7. The process as claimed in at least one of claims 1 to 6, wherein mixtures of potassiun fluoride and cesium fluoride which contain approximately 10 % by weight of cesium fluoride are employed as alkali metal fluorides.

8. The process as claimed in at least one of claims 1 to 5, wherein tetramethylammonium fluoride, tetra-n-butylammoniurn fluoride and/or tetra-n-octyl-ammonium fluoride are employed as tetraalkylammonium fluorides.

9. The process as claimed in at least one of claims 1 to 8, wherein quaternary ammonium or phosphonium compounds are employed as phase transfer catalysts.

10. The process as claimed in at least one of claims 1 to 9, wherein tetraalkyl(C1-C18)ammonium chlorides, tetraalkyl(C1-C18)ammonium bromides or tetraalkyl-(C1-C18)ammoniurn fluorides, tetraalkyl(C1-C18)-phosphonium chlorides or tetraalkyl(C1-C18)-phosphonium bromides, tetraphenylphosphonium chloride or tetraphenylphosphonium bromide or (phenyl) m ( alkyl(C1-C18 )n-phosphonium chlorides or (phenyl)m(alkyl(C1-C18))n-phosphonium bromides, where m is 1 to 3, n is 3 to 1 and m+n is 4, are employed as phase transfer catalysts.

11. The process as claimed in at least one of claims 1 to 10, wherein the quaternary ammonium or phos-phonium compounds used as phase transfer catalysts are employed in amounts of approximately 0.01 to approximately 50 mol % relative to 2,4-dichloro-5-fluorobenzonitrile.

12. The process as claimed in at least one of claims 1 to 8, wherein oligo- or polyethylene glycol dimethyl ethers which contain approximately 4 to approxi-mately 150 glycol units in the molecule are used as phase transfer catalysts.

13. The process as claimed in at least one of claims 1 to 8 and 12, wherein the oligo- or polyethylene glycol dimethyl ethers used as phase transfer catalysts are employed in amounts of approximately 0.5 to approximately 200 % by weight, relative to alkali metal fluoride or tetraalkyl(C1-C18)ammonium fluoride employed.

14. The process as claimed in at least one of claims 1 to 13, wherein the reaction is carried out under subatmospheric, superatmospheric or atmospheric pressure.

15. The process as claimed in at least one of claims 1 to 14, wherein the resulting 2,4,5-trifluoro-benzonitrile is continuously distilled off during the reaction.