United States Patent (19) 11 Patent Number: 5,463,135 Kanschik-Conradsen Et Al
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US005463135A United States Patent (19) 11 Patent Number: 5,463,135 Kanschik-Conradsen et al. 45) Date of Patent: Oct. 31, 1995 (54) FLUORINATED BENZILS AND A PROCESS OTHER PUBLICATIONS FOR THER PREPARATION European Search Report No. 93117299.1, Dec. 15, 1993, (75) Inventors: Andreas Kanschik-Conradsen, Chemical Abstract, vol. 076, No. 9, Feb. 28, 1972, No. Garbsen; Theodor Papenfuhs, 041832. Frankfurt am Main, both of Germany Chemical Abstracts, vol. 117, No. 23, Dec. 7, 1972, No. 2333927. 73) Assignee: Hoechst Aktiengesellschaft, Frankfurt, Chemical Abstracts, vol. 077, No. 23, Dec. 4, 1972, No. Germany 151617. (21) Appl. No.: 147,826 (List continued on next page.) (22 Filed: Nov. 4, 1993 Primary Examiner-James H. Reamer Attorney, Agent, or Firm-Connolly and Hutz (30) Foreign Application Priority Data Nov. 4, 1992 DE Germany .......................... 42 37 200.3 57 ABSTRACT (51) Int. Cl. .................................... C07C 49/784 Fluorinated benzils and a process for their preparation A 52 U.S. Cl. .......................... 568/331; 568/316; 568/332; process for the preparation of fluorinated benzils of the 568/306; 558/415 formula (1) 58) Field of Search ..................................... 568/316, 331, 568/306, 332, 331; 558/415 R3 X X6 (1) (56) References Cited / V-R X2 - C X5 U.S. PATENT DOCUMENTS R1 O R4 3,979,576 9/1976 Janson ..................................... 219/489 4,008,232 2/1977 Lacefield ........ ... 260/247.1 X3 X4 4,124,726 11/1978 Hamazaki et al. ...................... 568/331 in which X-X, R, R2, R and Ra are hydrogen, fluorine, 4,144,726 11/1978 Kuesters et al. ........................ 568/331 chlorine or bromine atoms, or alkyl (C-C), phenyl or 4,453,009 6/1984 Yamaguchi et al. .................... 568/316 naphthyl groups which may be substituted, or are groups 4,612,322 9/1986 Ogata et al. ............................ 568/331 reducing the electron density, at least one of the substituents 4,950,795 8/1990 Husler et al. ........................... 568/33 X-X being a fluorine atom, by reacting 1 mol of a benzil of the formula (1), in which X-X and R and R2 have the FOREIGN PATENT DOCUMENTS abovementioned meanings, with the proviso that at least one 745657 6/1970 Belgium ................................ 568/331 of the substituents X-X is a chlorine atom, with about 0.8 01.01760 2/1986 European Pat. Off.. to about 2.5 mol of potassium fluoride, rubidium fluoride, 0214565 8/1986 European Pat. Off. ............... 568/316 cesium fluoride or tetraalkyl (C-C)-ammonium fluoride 0227088 7/1987 European Pat. Off.. per chlorine atom to be exchanged, at temperatures of from 0191185 3/1990 European Pat. Off.. 2732149 2/1978 Germany. about 100° C. to about 280° C., possibly in the presence of 3420743 12/1985 Germany. a phase transfer catalyst and a dipolar aprotic or nonpolar 3637156 10/1986 Germany. solvent, and the new benzils prepared by this process. 3600891 7/1987 Germany. 60-72885 4/1985 Japan. 1265052 3/1972 United Kingdom ................... 568/316 10 Claims, No Drawings 5,463,135 Page 2 OTHER PUBLICATIONS Yakobson et al., (Mar. 1983). J. Med. Chem. 31 (1988) 983-991. Chemical Abstract, vol. 75,s No. 9, J. Md. Chem. 71,s vol. 14 J. Org. Chem. 23 (1958) 1539-1541. (11) pp. 1138-1140 Un. Tehran (1971). Jule. Chem. Acta 38 (1955) 46, 66. Chem. Abstract vol. 117, No. 23, Tetrahedron 92, vol. 48, J. Org. Chem. 23 (1958), 1306. pp. 7265 74 Univ. Liverpool, (1992). J. Am. Chem. Soc. 69 (1947) 667. Chemical Abstract vol. 77, No. 23, J. Chem. Soc. Perkin Advanced Org. Chem. J. Mar, 3rd Edition, 1985,969. Trans. 1 (JCPRB4), 72 (19) pp. 2426-2429 Univ. Durham Synthesis 1983, 169-184. "Alkali Metal Fluorides . , ', (1973). 5,463,135 1 2 FLUORINATED BENZILS AND A PROCESS FOR THER PREPARATION R3 X X6 (1) The present invention relates to a new and advantageous O R2 process for the preparation of fluorinated benzils by halex X2 G- X5 (chlorine-fluorine) exchange reaction from the correspond R1 O R4 ing chlorinated compounds, some of which are new. X3 X4 Fluorine-containing benzils are intermediates in the in which X1, X2, X3, X, Xs, X, R1, R2, R3 and R4 are preparation of pharmaceutical active ingredients. Thus, for 10 hydrogen, fluorine, chlorine or bromine atoms, alkyl(C- example, 4,4'-difluorobenzil is used to prepare antiinflam Co) groups, alkoxy(C-C) groups, substituted or unsub matory compounds (U.S. Pat. Nos. 4,008,232; 3,979,576). stituted aryl groups such as, for example, phenyl or naphthyl In addition, benzils can be converted, by cleaving the central groups which may be substituted by fluorine, chlorine or C-C bond by, for example, oxidation with atmospheric bromine atoms, or by alkyl(C-C), alkoxy (C-C), nitro, 15 cyano, -CHO,-COCl, -COF, -CF, -SO-alkyl(C oxygen (DE-A 2732149), into two benzoic acids which 1-C), -SOF, -SOCl, -COO-alkyl (C-C), -CON may be different and of which one contains at least one (alkyl (C-C)), -CO-phenyl or -SO, phenyl groups, or fluorine atom which has been introduced in the context of groups reducing the electron density, such as, for example, the process according to the invention. This is a possible nitro, cyano, -CHO,-COCl, -COF, -CF, -SO-alkyl route to, for example, valuable trihalobenzoic acids, such as 20 (C-C), -COF, -SOCl, -CONCalkyl (C-C)), 2-chloro-4,5-difluorobenzoic acid or 2,4,5-trifluorobenzoic -COO-alkyl(C-C), -CO-phenyl or -SO-phenyl acid, which are used as precursors to antibacterial agents groups, with the proviso that at least one of the substituents (EPA227 088; DE-A3 600 891; DE-A3420743; EP-A 191 X-X is a fluorine atom, can be prepared in an advanta 185; JP 60 072885; J. Med. Chem. 31, (1988), 983-991). geous manner by reacting 1 mol of a benzil of the above 25 mentioned formula (1) in which X-X and R, R2, R and Such compounds have previously been prepared in a R have the meanings mentioned, with the proviso that at variety of ways from starting compounds which already least one of the substituents X-X is a chlorine atom, with contain fluorine. Thus, for example, 2,2'-difluorobenzil can from about 0.8 to about 2.5 mol of potassium fluoride, be prepared by benzoin condensation from 2-fluorobenzal rubidium fluoride, cesium fluoride or tetraalkyl (C-C)- dehyde with subsequent oxidation (J. Org. Chem. 23, 1958, 30 ammonium fluoride or mixtures thereof per chlorine atom to 1539-1541). The use of fluorinated benzaldehydes makes be exchanged at temperatures of from about 100 to about this synthesis route uneconomic and hence unattractive. 280° C., preferably from about 160° to about 240° C., in the 4,4'-Difluorobenzil can be obtained by, for example, a five absence or presence of a phase transfer catalyst and in the stage synthesis from fluorobenzene and chloral (Helv. Chim. absence or presence of a dipolar aprotic or nonpolar solvent. 35 The dipolar aprotic solvents employed in the process Acta 38 (1955), 46, 66; J. Org. Chem. 23 (1958), 1306; J. according to the invention may be sulfolane (tetramethylene Am. Chem. Soc. 69 (1947) 667). Due to the large number of sulfone), tetramethylene sulfoxide (TMSO), N,N-diethylac stages, the use of cyanides, and the use as starting material etamide, N,N-dimethylacetamide (DMAc), N,N-dimethyl of fluorobenzene-which depending on the market situation formamide (DMF), N-methylpyrrolidone (NMP), dimethyl may be difficult to obtain and/or available at unfavorable sulfoxide (DMSO), dimethyl sulfone, diphenyl sulfoxide, cost-this synthesis route is costly and unsuitable. diphenyl sulfone, tetramethylurea, tetra-n-butyl urea, 1,3- There was therefore a considerable demand for a more dimethylimidazolidin-2-one (DMI) or mixtures thereof. favorable synthesis route. Examples of suitable nonpolar solvents are chloronaptha Halex (chlorine-fluorine) exchange reactions in chlori lene, dichlorobenzene, toluene or xylenes. nated benzaldehydes have been known for a number of years 45 The fluoride salts employed are potassium, rubidium, cesium or tetraalkyl (C-C)-ammonium fluoride or mix (DE-A3637156). The preparation of fluorinated benzophe tures thereof in amounts of from about 0.8 to about 2.5 mol nones, for example 4,4'-difluorobenzophenone, by halex of fluoride per chlorine atom to be exchanged, preferably reaction is also known in principle (EP 101 760). By from about 0.9 to about 1.5 mol and particularly preferably contrast, the preparation of fluorinated benzils by this syn 50 from about 1.0 to about 1.2 mol. Potassium fluoride and thetic principle has not been described up to now. The main mixtures of potassium fluoride and cesium fluoride are reasons which may account for this are described briefly preferred; potassium fluoride is particularly preferred. The below. It has long been known from the literature that process according to the invention permits the use of a aromatic O-diketones, when treated with bases, are rear spray-dried fluoride salt, although this is not necessary to ranged to give o-hydroxycarboxylic acids (benzil-benzilic 55 achieve good results. acid rearrangement, Advanced Organic Chemistry, J. March, The process according to the invention can be carried out either with or without the addition of a phase transfer 3rd Ed., J. Wiley ed., N.Y. (1985), 969). However, since catalyst. However, in some cases the use of phase transfer alkali metal fluorides in aprotic systems are very strong catalysts enables virtually quantitative and considerably bases (Yakobson et al., Synthesis (1983), 169), there was a 60 accelerated conversion. Suitable phase transfer catalysts are definite possibility for the reaction of, for example, 4,4'- quaternary ammonium or phosphonium compounds such as dichlorobenzil with an alkali metal fluoride to lead not to the tetraalkyl (C-C)-ammonium chlorides, bromides or fluo desired 4,4'-difluorobenzil but instead at least partially to rides, tetraalkyl (C-C)-phosphonium chlorides or bro undergo a side reaction to give 4,4'-dichlorobenzilic acid mides, tetraphenylphosphoniumchloride or bromide, fluoride or its secondary products.