CA1190559A - Process for producing fluorobenzophenone derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

4-Fluorobenzophenone derivatives or 4,4'-difluoro-benzophenone are produced by effecting a halogen-fluorine exchanging reaction between the corresponding 4-halogeno-benzophenone derivatives or 4,4'-dihalogenobenzophenone and an alkali fluoride. The reaction is carried out by heating in an organic solvent. After distilling off the solvent from the reaction product mixture, the end product is isolated by extracting with a solvent. Alternatively the end product is isolated by distillation.

Description

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PROCESS FOR PRODUCING FLUOROBENZOPHENONE DERIVATIVES
-BACKGROUND OF THE INVENTION:
This invention relates to a process for the production of fluorobenzophenone derivatives and particularly, 4-fluorobenzophenone derivative and 4,4'-difluorobenzo-phenone.
Fluorobenzophenone derivatives, for example 4,4'-difluorobenzophenone are used as materials for producing an aromatic polyketone polymer and 4-fluorobenzophenone derivatives are useful for agricultural chemicals and drugs and intermediates for dyestuffs.
For producing 4,4'-difluorobenzophenone, there have been known, for example, (1) a process of reacting fluoro-benzene with carbon tetrachloride in the presence of anhydrous aluminum chloride and then hydrolyzing EJ . P .
Picard et al, Can. J. Research, 28B, 56 ~1950); C.A., 44, 4442a (1950); Funasaka et al, Yukigoseikagaku Kyokaishi, 17, 334 (1959)], (2) a process of effecting Friedel-Crafts' reaction 3~

between p-fluorobenzoylchloride and Eluorobenzene in the presence of anhydrous aluminum chloride [R. C. Iris et al, Rev~ inst. Salubridad y enfermeded. trop , 8, 63 (1947); C.
A., 42, 1921 a (1948)], (3) a process of oxidizing 2,2'-bis(4-~luorophenyl)-1,1-aichloroethylene with chromic aciâ
[~-1. L. Bradlow et al, J. Am. Chem Soc., 69, 662 (1947)] and (4) a process of treating 4,4'-diaminodiphenylmethane with sodium nitrite in anhydrous hydrogen fluoride or in a concentrated aqueous solution of hydrogen fluoride (Japanese lO Patent Application Kokai No. 54-132,558).
Also, for producing 4-fluorobenzophenone derivatives there have ~een known, for example, (5) a process of effecting Friedel-Crafts' reaction between a substituted benzoylchloride and fluorobenzene in the presence of anhydrous aluminum 15 chloride ~R. D. Dunlop et al, J. Am. Chem. Soc , 55, 1665 (1933); K. C. Joshi et al, J> Indian Chem. Soc., 40, ~2 (1963); R. G. Pews et al, J. Am. Chem. Soc., 89, 2392 (1967)]
and (6) a process of reacting p-fluorobenzoylchloride with an aromatic hydrocarbon in the presence of anhydrous aluminum chloride [Z. Eckstein et al, Bull acad. polon. sci , Ser.
sci., chim., geol. et geograph., 7, 803 (1959); Chem. Abstr.
54, 21005 b (1960)].
However, in case of the processes (1) and (2) fluorobenzene is an expensive material and anhydrous aluminum chloride of more than equimol relative to fluorobenzene is required. Also, the separation oE the catalyst is too complicated to reuse it and further, appara-tus of anti-corrosion are required.
In case of the process (3) fluorobenzene is used as a starting material and a large amount of glacial acetic 5~
acid is necessary. Also, since an excess of anhydrous chromic acid is used, a load for treating waste fluid generated to non-pollution becomes heavy.
In case of the process (4) the starting materials are of relatively low costs, while since a large excess of anhydrous and concentrated hydrogen fluoride is used, the recovery of hydrogen fluoride is necessary.
Further, the apparatus for production made of specific materials such as a reaction and recovery vessel of anti-corrosion are required and also, the toxicity of hydrogenfluoride should be taken into consideration~
In case of the processes (5) and (6) fluorobenzene and p-fluorobenzoylchloride are expensive industrially and anhydrous aluminum chloride of more than equimol is neces-sary. The separation of the catalyst is too complicated toreuse it and also, the load for treating waste fluid gener-ated is heavy~ Therefore, conducting these processes in a commercial scale is confronted with various difficulties.
An object of this invention is to provide a process for producing 4-fluorobenzophenone derivatives or 4,4'-difluorobenzophenone conveniently in a commercial scale starting from the corresponding 4-halogenobenzophenone derivatives or 4r4'-dihalogenobenzophenone.
In accordance with this invention there is provided a process for the production of 4-fluorobenzophenone derivatives or 4,4'-difluorobenzophenone which comprises effecting a halogen-fluorine exchanging reaction between 5~

a 4 halogenobenzophenone derivatives of Formula I.

X ~ - C ~
O Rn wherein X is chlorine, bromine or iodine atom, R is hydrogen,' an alkyl group, an aralkyl group, a cycloalkyl group, an aryl group, an alkoxyl group, an aryloxyl group, an alkylthio group, a carboalkoxyl group, an acetyl group, a trifluoro-methyl group~ a nitro group or a halogen atom provided the halogen is substituted on positions other than the 4'-position, and n is an integer of 1-5 and when n is 2 or more, R may be the same or different or 4,4'-dihalogeno benzophenone of Formula II, X ~ C ~ -X II

wherein X is a chlorine, bromine or iodine atom and an alkali fluoride.
According to this invention, the corresponding 4 fluorobenzophenone derivatives or 4,4'-difluorobenzophenone are produced with a high yield by heating the 4-halogeno-benzophenone derivative of Formula I or 4,4'-dihalogenoben-zophenone of Formula II and an alkali fluoride in an organic solvent. After distilling off the solvent from the reaction product mixture, the end product is isolated easily by extracting with a solvent. Alterna~ively, the end product is isolated by distillation. Therefore the process of this invention is quite advantageous industrially.

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The 4-halogenobenzophenone derivatives of Formula I
which may be used in this invention are, for example, 4-halogenobenzophenone, 4-halogeno-3'-methylbenzophenone, 4-halogeno-4'-methylbenzophenone, 4-halogeno-4'-ethyl-benzophenone, 4-halogeno-4'-n-butylbenzophenone, 4-halogeno-

2',4'-dimethylbenzophenone, 4-halogeno-2',5'-dimethyl-benzophenone, 4-halogeno-4'-phenylbenzophenone, 4-halogeno-4'-methoxybenzophenone, 4-halogeno-4l-ethoxybenzophenone, 4-halogeno-4'-phenoxybenzophenone, 4-halogeno-4'-methyl-thiobenzophenone, 4-halogeno-3'-carbomethoxybenzophenone, 4-halogeno-3'-acetylbenzophenone, 4-halogeno 3'-trifluoro-methylbenzophenone, 4~halogeno-3'-nitrobenzophenone, 4-halogeno-4'-nitrobenzophenone, 2-chloro-4'-halogenobenzo-phenone, 2-bromo-4'-halogenobenzophenone, 3-chloro-4'-halogenobenzophenone, 4-halogeno-3',5'-dichlorobenzophenone, or the 4,4'-dihalogenobenzophenone of Formula II which may be used in this invention are 4,4'-dichlorobenzophenone, 4,4'-dichlorobenzophenone, 4,4'-dibromobenzophenone and 4,4'-diiodobenzophenone.
These 4-halogenobenzophenone derivatives of Formula I
may be prepared by effecting Friedel-Crafts' reaction between p-chloro-, p-bromo- or p-iodo-benzoyl chloride and an aromatic hydrocarbon which are both available easily in a commercial scale or between a substituted benzoylchloride and chlorobenzene, bromobenzene or iodobenzene in the presence of an anhydrous ferric chloride catalyst.

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The alkali fluorides which may be used in this invention are, for example, cesium fluoride, rubidium fluoride, potas-sium fluoride, sodium fluoride and lithium fluoride. Taking the yield of end product into consideration, cesium fluoride, rubidium fluoride and potassium fluoride are preferred. These may be used in mixture of two or more. The amount of the alkali fluoride for attaining the halogen fluoride exchanging reaction is not particularly limited, though a small excess over the stoichiometrical amount is preferred. The amount may be decided according to the yield and economy.
The organic solvent used in this invention is, for examp]e, a sulphur-containing polar soLvent e.g. dimethyl sulfoxidet dimethyl sulfone, diphenyl sulfoxide, diphenyl sulfone, tetra-hydrothiophene~ dioxide ~sulfolane) and a nitrogen-contain-ing polar solvent e~g., N,N-dimethylformamide, N,N-dimethyl-acetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone (DMI) and hexa~ethylphosphoric acid triamide ~HMPA) and other non-proton polar solvents.
The reaction temperature is, in general, between 100 and 350Co The progress of the reaction is traced by a gas chromatography or thin layer chromatography and the end of the reaction is when most of the starting materials has disappeared.
The process of this invention is carried out by heating the 4-halogenobenzophenone derivativess of Formula I or 4141-dihalogenobenzophenone of Formula II, and alkali fluoride in the organic solvent under stirring. In this case, an inter-layer moving catalyst such as a large ring polyether (crown ether), quaternary ammonium salts and quaternary phosphonium salts may be added to stabilize an alkali metal cation.
According to a preferred embodiment of this invention, a small amount of benzene is added to the organic solvent containing the 4-halogenobenzophenone derivatives of Formula I or ~,4'-dihalogenobenzophenone of Formula II and alkali fluoride and heated.
Water in the reaction system is removed in the form of an azeotropic mixture with benzene and thereafter, heating is continued at indicated temperatures under stirring, which is effected, preferably under nitrogen atmosphere to prevent the solvent from decomposing.
After indicated reaction time, the resuLtin~ products are cooled and the end compound is extracted by an organic solvent.
Examples of the solvent for extraction include alcohols such as methanol, ethanol and isopropanol, halogenated hydro-carbons such as 1,2-dichloroethane, chloroform and carbon tetrachloride and benzenes such as benzene and toluene.
Alternatively, after completion of the reaction the solvent is distilled off under reduced pressure and then, the residues are subject to extraction with the above extraction solvent to isolate the end product~ Also, the end product is isolated directly with the distillation under reduced pressure. If necessary, a product oE high purity can be obtained from a conventional solvent recrystallization.

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As mentioned above, the corresponding 4-fluorobenzo~
phenone derivatives having only a halogen substituent on 4-position exchanged for fluorine can be obtained starting from 4-halogenobenzophenone derivatives of Formula I and the cor-responding 4,4'-difluorobenzophenone having both halogen atoms on 4- and 4'-positions exchanged for fluorine can be obtained starting from 4,4'-dihalogenobenzophen'one of Formula II.
This invention will be illustrated by the following non-limitative examplesO
Example 1 To a mixture of 10.1 g (0.04 mols) of 4,4'-dichloro-benzophenone, 9.3 g (0.16 mols) of potassium fluoride and 20 g of dimethyl sulfone were 5 ml of benzene added. Water in the reaction system was removed together with benzene by azeotropy. The reaction was carried out under nitrogen atmosphere at temperatures of 230-240C while stirring for 45 hours.
After cooling, the reaction product was extracted under heating twice with 15 ml of isopropanol. When the extracts together were placed to cool, 7.0 g of 4,4'~difluorobenzo-phenone was obtained.
Yield 80~, Melting point 106-107C.
Pure product was obtained from recrystallisation with a methanol/water (80/20) mixture. Melting point 106-107C.

- 7a -Elementary Analysis C(%) H(%) F(%) Calculated 71.5 3.70 17.4 Found 71.2 3.50 17.2 Exam~le 2 To a mixture of 10.1 g (0.04 mols) of 4,4'-dichlorobenzophenone, 9.3 g (0.16 mols) oE potassium fluoride and 20 g of dimethyl sulfone were 5 ml of benzene added and water in the reaction system was removed together with benzene by azeotropy. 0.5 g of Dibenzo-18-crown-6-ether were added thereto and the reaction was carried out under nitrogen atmosphere at tempera-tures of 230-240C while stirring for 30 hours. The post treatment is effected in the same manner as in Example 1. 7.U g of 4,4'-difluorobenzophenone were obtained.
Yield 80%, M.P. 106-l07C
Fxample 3 Using 13.b g (0.04 mols) of 4,4'-dibromo-benzophenone, 9.~ g (0.16 mols) of potassium fluoride and 20 g of dimethyl sulfone r 6.8 g of 4r~-difluorobenzophenone were obtained in the same procedure as in Example 1.
Yield 78~, M.P. 106-107C

To a mixture oE 10.1 g (O.U4 mols) of 4,4'-dichlorobenzophenone, 7.0 g (0.l2 mols) of potassium ~luoride and 25 g of sulfolane were 5 ml of benzene added and water - in the reaction system was removed together with benzene by azeotropy.
The reaction was carried out under nitrogen atmosphere at temperatures of 273-277C while StirrinCJ for ten hours. After cooling the sulfolane was distilled off i5~
under reduced pressure. The residues were extracted under heating twice with 20 ml of isopropanol. When the extracts together were placed to cool, 5.7 g of 4,4'-difluoro-benzophenone were obtained.
Yield 65%, M.P. 106-107C
Exam~le 5 To a mixture of 10.1 g (0.04 mols) of 4,4'~
dichlorobenzophenone, 15.2 g (0.1 mol) of cesium fluoride and 25 g of sulfolane were 5 ml of benzene added and water in the reaction system was removed together with benzene by azeotropy.
The reaction was carried out under nitrogen atmosphere at temperatures of 200-210C while stirring for ten hours. After cooling the pos-t-treatment is effected in the same manner as in Example 4 and thus, 7.4 g of 4,4'-difluorobenzophenone were obtained.
Yield 85%, M.P. 106-107C
Example 6 To a mixture of 20.~ g (0.08 mols) of 4,4'-dichlorobenzophenone, 30.4 g (0.2 mols) of cesium fluoride and 50 g of N-methylpyrrolidone were 10 ml of benzene added and water in the reaction system was removed together with benzene by azeotropy.
The reaction was carried out under nitrogen atmosphere at temperatures of 200-202C while stirring for - 20 hours. AEter cooling the N-methylpyrrolidone was distilled off under reduced pressure. 12 g of 4,4'-Difluorobenzophenone were obtained by distillation under reduced pressure.
Yield 70~, M.P. 105-106C
Boiling Point 150-155C/12 ~m~g _ 9 _ ~lD5~
Pure product was obtained from recrystallization with isopropanol.
M.P. 106--107C
Exam~le 7 To a mixture of 10.1 g (O.u4 mols) of 2,4'-dichlorobenzophenone, 4.6 g (û.û8 mols) of potassium fluoride and 20 g of dimethyl sulfone were 5 ml oE benzene added and water in the reaction system was removed together with benzene by azeotropy.
The reaction was carried out under nitrogen atmosphere at'temperatures of 230-24ûC while stirring for 11 hours. After cooling the reaction product was extracted under heating twice with 20 ml of isopropanol. The extracts together were placed to cool and thus, 7.5 g of 2-chloro-4'-fluorobenzophenone were obtained.
Yield 80~, M.P. 60-61C
Pure product was obtained from recrystallization with isopropanol.
M.P. 60-61C
Exa ~
Using O.u4 mols of 4-chlorobenzophenone derivatives, the reaction was carried out in the same procedure as in Example 7 to obtain the corresponding 4-fluorobenzophenone derivatives. The results obtained are set forth in Table 1.

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Table 1 Ex. 4-FluorobenzophenoneYield M P.
No. clerivatives (~) (C) ,, . ~
8 4-Fluorobenzophenone 86 49-50 5 9 4-Fluoro-3'-methylbenzophenone 81 97-98 4-Fluoro-4'-n-butylbenzophenone 78 75-76 11 4-Fluoro-4'-phenylbenzophenone 80 148-l49 12 4-Fluoro-4'-e-thoxybenzophenone 72 87-88 13 4-Fluoro-3'--trifluoromethyl- 82 100--l01 benzophenone __ ~ ... ~.. . .. _ ___ _ _ Example 14 To a mixture of 12.2 g (O.U5 mols) of 4-chloro-2~,4'-dimethylbenzophenone, 12.1 g (0.08 moLs) of cesium fluoride and 20 g of N-methylpyrrolidone were 5 ml of benzene added and water in the reaction system was removed together with benzene by azeotropy. The reaction was carried out under nitrogen atmosphere under reflux by heating while stirring for 15 hours. ~fter cooling, the reaction product obtained was poured into 100 ml of water and then, extracted with 50 ml of~diethyl ether and further with 50 ml of e-ther. The extracts together were dried and distilled and thus, 8.9 g of 4-~luoro-2',4'-dimethylbenzophenone were obtained.
~ield 78%, B.P. 151-152C/10 mmHg ExamELe 15 To a mixture of 14.4 g (0.05 mols) of 4-bromo-2',5'-dimethylbenzophenone, 5.5 g (0.095 mols) of potassium fluoride, 0.06 g (0.005 mols) of cesium fluoride and 20 g of sulfolane were 5 ml of benzene added and water in the reaction system was removed together with benzene by ;i5~
azeotropy.
The reaction was carried out under nitrogen atmosphere at temperatures of 245-250C while stirring for 15 hours. After cooling, the reaction products were poured into 100 ml of water and then, extracted with 50 ml of diethyl ether and further with 50 ml of ether. The extracts together were dried and distilled and thus, 7.8 g of 4-fluoro-2',5'-dimethylben~ophenone were obtained.
Yield 69%, B.P. 164-166C/10 mmHg ...... . . . .. .

Claims (4)

Claims:

1. A process for producing fluorobenzophenone derivatives or 4,4'-difluorobenzophenone which comprises reacting (a) 4-halogenobenzophenone derivatives of Formula I, I

wherein X is chlorine, bromine or iodine atom, R is hydrogen, an alkyl group, an aralkyl group, a cycloalkyl group, an aryl group, an alkoxy group, an aryloxyl group, an alkylthio group, a carboalkoxyl group, an acetyl group, a trifluoromethyl group, a nitro group or halogen atom provided that the halogen is sub-stituted on other positions than 4'-position, n is an integer of 1-5 and when n is 2 or more, R is the same or different or 4,4'-dihalogenobenzophenone of Formula II

II

wherein X is a chlorine, bromine or iodine atom, and (b) an alkali fluoride.

2. The process of claim 1 wherein said halogen-fluorine exchanging reaction is carried out in an organic solvent at temperatures of 100-350°C.

3. The process of claim 1 wherein said alkali fluoride is at least one member selected from lithium fluoride, potassium fluoride, sodium fluoride, rubidium fluoride and cesium fluoride.

4. The process of claim 1 wherein said halogen-fluorine exchanging reaction is carried out in the presence of an interlayer moving catalyst.