United States Patent (19) 3,941,802 Gall . (45) Mar. 2, 1976 54 2-(IMIDAZOL-1-YL)BENZOPHENONES

75 inventor: Martin Gall, Kalamazoo, Mich. 73) Assignee: The Upjohn Company, Kalamazoo, Mich. (22 Filed: Apr. 4, 1975 (21) Appl. No.: 565,107 52 U.S. C...... 260/309; 260/240 G; 260/340.9; 260/566 AE; 260/566 R; 260/.578; 260/999 (5) Int. Cl.’...... C07D 233/60 58 Field of Search...... 260/309 56 References Cited UNITED STATES PATENTS fluoro with the proviso that R cannot be fluoro, if R, 3,526,636 9/1970 Houlihan ...... 2601309 is chloro or trifluoromethyl; and wherein R is hydro 3,534,06 10/1970 Black...... 260/309 gen, fluoro, chloro, bromo, trifluoromethyl, or nitro, 3,763,178 l Of 1973 Sulkowski...... 2601309.6 are obtained by a multi-step reaction from the corre 3,763,179 0, 1973 Gall ...... 2601309 sponding a-(phenyl)-o-toluidine of the formula I Primary Examiner-Natalie Trousof Attorney, Agent, or Firm-Hans L. Berneis NHe

57 ABSTRACT H Compounds of the formulae IV and V: R4 H

Re Ra

wherein R, R and R are defined as above, by treat ing I in sequence with an alkyl ester of orthoformic acid the resulting product with 2-alkyl-2-(aminoalkyl)- W 1,3-dioxolane or a 2-amino-alkanone dialkyl ketal and finally with titanium tetrachloride to obtain compound IV, and oxidizing compound IV to obtain the corre sponding compound V. Compounds IV and V have minor tranquilizing activity which can be utilized to calm mammals or birds. Their more important use, however, is as wherein Ro and R1 are hydrogen or alkyl of 1 to 3 car intermediates in the production of the strongly bon atoms, inclusive; wherein R, is hydrogen, fluoro, sedating and tranquilizing imidazolobenzodiazepines. chloro, or trifluoromethyl; wherein R is hydrogen or 12 Claims, No Drawings 3,941,802 1 2-(MIDAZOL-1-Y L)BENZOPHENONES BRIEF SUMMARY OF THE INVENTION 1. Field of the Invention This invention is directed to new organic compounds 5 and more specifically to 1-(a-phenyl-0-tolyl)imidazoles and 2-(imidazol-i-yl)benzophenones and a process of the production therefor. The new compounds and the process therefor is illus tratively represented as follows: O

He

W

25

. from IV N-cCH-OR

35 Ro

40

from 45

Rs SO

55 wherein Ro and R are hydrogen or alkyl of 1 to 3 car bon atoms, inclusive; wherein R. is hydrogen, fluoro, chloro, or trifluoromethyl; wherein R is hydrogen or fluoro with the proviso that Rs is not fluoro if R is 60 chloro or trifluoromethyl; wherein R is hydrogen, fluoro, chloro, bromo, trifluoromethyl, or nitro; and wherein Rs is alkyl as defined above. The process of this invention comprises: heating a compound of formula 1 with a trialkyl orthoformate 65 wherein the alkyl group has from 1 to 3 carbon atoms, 3,941,802 3 inclusive, with or without an inert organic solvent to and obtain compound II; heating compound Il in an incrt organic solvent with an amino acetal or ketal VI

Ro H2N-CH sc49 R W R - wherein R and R are defined as above to obtain com O pound ill; treating at 0 to 20°C. compound III with - titanium tetrachloride in an inert organic solvent and heating subsequently the mixture to reflux to obtain R O VA compound IV; oxidizing compound IV to obtain com pound V. 15 Alternatively, compound II can be heated between Rf Re 25 to 78 C. in a lower alkanol (1 to 3 carbon atoms) with an aminoaldehyde diacetal or aminoketone di ketal of the formula VII: 20 R O OR N / N-C-C-R w wherein R'o and R' are hydrogen, methyl, or ethyl; 25 wherein R", is hydrogen, chloro, or fluoro; wherein R' wherein R and R are defined as above and R is is hydrogen or fluoro with the proviso that R's is not methyl or ethyl to give the compound illA: fluoro, if R", is chloro; and wherein R' is hydrogen, fluoro, chloro, or trifluoromethyl. The most preferred compounds of this invention are of the formula IVB and VB: Ra 0 St-c? O 30 N Re0 -NH NECH 35

WB

40 H R R"e

45 wherein R. R., R., R., R., and Rs are defined as above. Compound IIIA is cyclized in the same manner as com pound III with titanium tetrachloride. 2. Description of the Preferred Embodiment 50 and Lower alkyl groups of 1 to 3 carbon atoms, inclusive, are exemplified by methyl, ethyl, propyl, and isopropyl. The more preferred compounds of this invention are of the formulae IVA and VA: 55 R-1) R o -( WB H R 21 N 60 R". O H R"a WA R 65 R 3 R2 wherein R" is hydrogen or methyl; wherein R", is hydrogen or chloro; wherein R' is hydrogen, chloro, or fluoro. 3,941,802 5 6 As tranquilizing agents, compounds of formulae IV 24 hours to give the corresponding compound IIIA, or V can be used in unit dosage forms of 1 to 15 mg. per which can be used without further purification. kg and preferably in dosages of l to 10 mg/kg. In larger mammals, above 10 kg., the lower range of dos Compound III in pure form or in the crude form is age is preferred. dissolved in an inert organic solvent and titanium tetra As intermediates the compounds of formula V are chloride is added. The addition is generally performed first treated with formaldehyde in formalin to produce between zero and 20° C. with stirring during 5 to 30 a 2-(2-hydroxymethyl)imidazol-1-yl)benzophenone minutes. Thereafter the mixture is brought to reflux of the formula and kept at this temperature for 1 to 12 hours, to give 10 ihe corresponding compound IV. Compound IV is isolated and purified by conventional methods e.g. extraction, filtering, chromatography, and crystalliza tion. 5 Compound IV is oxidized to Compound V with a chromic acid oxidizing agent. In the preferred embodiment of this invention, the acetic acid solution of compound IV is admixed with Jones' reagent and the mixture is heated to reflux for 1 W 20 to 12 hours. After cooling the mixture is neutralized with a base, e.g. aqueous sodium or potassium hydrox ide or carbonate, and the product V recovered by ex traction. Conventional means, such as washing, filter ing with or without filter aids, chromatography and/or 25 crystallization are used to purify compound V. The following preparations and examples are illustra tive of the processes and products of the present inven tion, but are not to be construed as limiting. 30 Preparation 1 wherein R, R, R2, Ra, and R are defined as hereinbe 2-Amino-5-chlorobenzophenone hydrazone fore. Compound VIII is then treated e.g. with thionyl A mixture of 27.2 g (0.117 mol) of 2-amino-5- chloride to give the chloride of the alcohol VIII, and chlorobenzophenone in 170 ml. of diethylene glycol this compound is cyclized with ammonia to give the 35 and 23 ml. (0.45 mol) of 99% hydrazine hydrate is known end products 4H-imidazol,2-a 1,4)ben brought to reflux for a total of 7 hours. The solution is zodiazepines (Belgium Patent No. 787,251), which are allowed to cool overnight to room temperature. The important sedatives, hypnotics and tranquilizers. light green-colored solid which results is mixed with The starting compounds of formula I of this invention 40 400 ml. of water and extracted into benzene; the layers are synthesized as shown in the Preparations. are separated and the benzene portion dried over anhy The process of this invention comprises: heating a drous magnesium sulfate and concentrated. Crystalliza compound of formula I with an excess of a trialkyl tion of the residue from ether/hexane gives 13.5 g. orthoformate: In the preferred embodiment of this (46.8%) 2-amino-5-chlorobenzophenone hydrazone of invention the solution of compound I in the orthofor 45 mate acid ester is refluxed for 5 to 24 hours. Trimethyl melting point 133-133.5° C. or is preferred, but higher trialkyl Anal. calcd. for CHCIN: C, 63.55; H, 4.93; N, orthoformates can be used. The refluxing is continued 17.11; C, 14.43. Found: C, 63.58; H, 4.95; N, 7.32; until most of the alcohol i.e. methanol or respectively Cl, 14.39. is distilled. The resulting oil is the compound II 50 which is used without further purification. - Preparation 2 Compound II is dissolved in an inert organic solvent 2-Amino-2',5-dichlorobenzophenone hydrazone e.g. ethanol, methanol, propanol, and the solution is In the manner given in Preparation 1, 2-amino-2',5- treated with an excess of 2-alkyl-2-(1-aminoalkyl)-1,3- dichlorobenzophenone is refluxed with hydrazine hy dioxolane VI. The mixture is refluxed during % to 3 55 drate in diethylene glycol to give 2-amino-2,5- hours. Thereafter all volatile liquids are removed pref dichlorobenzophenone hydrazine. erably by vacuum distillation, and the residue is puri fied by conventional means, such as washing with or Preparation 3 ganic solvents, filtration, crystallization or the like to give the purified product of formula III. 60 2-Amino-5-chloro-2',6'-difluorobenzophenone Instead of using an amino compound of formula VI hydrazone an aminoacetal or aminoketal of formula VII can be In the manner given in Preparation 1, 2-amino-5- used. The reaction is usually carried out by reacting a chloro-2',6'-difluorobenzophenone is refluxed with solution of compound II in methanol or ethanol solu hydrazine hydrate in diethylene glycol to give 2-amino tion between 25 to 78° C. with compound VII for 1 to 5-chloro-2',6'-difluorobenzophenone hydrazone. 3,941,802 7 8 trated to yield an orange oil. Distillation affords 9.9 g, Preparation 4 of 2-benzyl-4-chloroaniline (89.2%) yellow oil of boil 2-Amino-2'-chloro-5-nitrobenzophenone hydrazone ing point 125-140°C. (at 0.1 mm Hg). In the manner given in Preparation 1, 2-amino-2'- Anal. calcd. for CHCIN: C, 71.72; H, 5.56; N, chloro-5-nitrobenzophenone is refluxed with hydrazine 5 6.44; C, 16.28. Found: C, 71.55; H, 5.51; N, 6.58; Cl, hydrate in diethylene glycol to give 2-amino-2'-chloro 16. 6. 5-nitrobenzophenone hydrazone. Preparation 12 Preparation 5 O 2-(0-Chlorobenzyl)-4-chloroaniline 2-Aminobenzophenone hydrazone In the manner given in Preparation 1 1,2-amino-2,5- In the manner given in Preparation 1, 2-aminoben dichlorobenzophenone hydrazone is refluxed with po zophenone is refluxed with hydrazine hydrate in dieth tassium hydroxide in diethylene glycol to give 2-(0- ylene glycol to give 2-aminobenzophenone hydrazone. chlorobenzyl)-4-chloroaniline, melting point 64-65 15 Preparation 6 C. 2-Amino-2'-chlorobenzophenone hydrazone Preparation 13 In the manner given in Preparation 1, 2-amino-2'- 4-Chloro-a-(2,6-difluorophenyl)-0-toluidine chlorobenzophenone is refluxed with hydrazine hy In the manner given in Preparation 11, 2-amino-5- drate in diethylene glycol to give 2-amino-2'- chloro-2',6'-difluorobenzophenone is refluxed with chlorobenzophenone hydrazone. potassium hydroxide in diethylene glycol to give 4 Preparation 7 chloro-a-(2,6-difluorophenyl)-0-toluidene. 5-Fluoro-2-aminobenzophenone hydrazone 25 Preparation 14 In the manner give in Preparation 1, 5-fluoro-2- 2-(0-Chlorobenzyl)-4-nitroaniline aminobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 5-fluoro-2-aminobenzophe In the manner given in Preparation l 1, 2-amino-2'- none hydrazone. chloro-5-nitrobenzophenone hydrazone is refluxed 30 with potassium hydroxide in diethylene glycol to give Preparation 8 2-(0-chlorobenzyl)-4-nitroaniline. 2-Amino-5-chloro-2'-fluorobenzophenone hydrazone Preparation 15 In the manner given in Preparation 1, 2-amino-5- 2-benzylaniline chloro-2'-fluorobenzophenone is refluxed with hydra zine hydrate in diethylene glycol to give 2-amino-5- 35 In the manner given in Preparation 11, 2-aminoben chloro-2'Fluorobenzophenone hydrazone. Zophenone hydrazone is refluxed with potassium hy droxide in diethylene glycol to give 2-benzylaniline. Preparation 9 Preparation 16 5-(Trifluoromethyl)-2-aminobenzophenone hydrazone 40 2-(0-Chlorobenzyl)aniline In the manner given in Preparation 1, 5-)trifluorome thyl)-2-aminobenzophenone is refluxed with hydrazine In the manner given in Preparation l 1, 2-amino-2'- hydrate in diethylene glycol to give 5-trifluoromethyl chlorobenzophenone hydrazone is refluxed with potas 2-aminobenzophenone hydrazone. sium hydroxide in diethylene glycol to give 2-(0- 45 chlorobenzyl)aniline. Preparation 10 2-Amino-3'-chloro-5-nitrobenzophenone hydrazone Preparation 17 In the manner given in Preparation 1, 2-amino-3'- 4-fluoro-a-(2,6-difluorophenyl)-0-toluidine chloro-5-nitrobenzophenone is refluxed with hydrazine In the manner given in Preparation 11, 2-amino-2',5- hydrate in diethylene glycol to give 2-amino-3'-chloro 50 6'-trifluorobenzophenone is refluxed with potassium 5-nitrobenzophenone hydrazone. hydroxide in diethylene glycol to give 4-fluoro-o-(2,6- Preparation 11 difluorophenyl)-0-toluidene. Preparation 8 2-Benzyl-4-chloroaniline 55 Potassium hydroxide pellets (6.1 g. 287 mmol) are 2-(0-Fluorobenzyl)-4-chloroaniline ground and dissolved in 85 ml. of refluxing diethylene In the manner given in Preparation 1 1, 2-amino-2'- glycol. Volatile materials are distilled until the temper fluoro-5-chlorobenzophenone hydrazone is refluxed ature of the liquid reached 200°C. The solution is then with potassium hydroxide in diethylene glycol to give cooled to room temperature and 13.5 g. (54.6 mmol) 60 2-(0-fluorobenzyl)-4-chloroaniline. of 2-amino-5-chlorobenzophenone hydrazone is added while the syrupy liquid is gently reheated. At 100° C. all Preparation 19 the hydrazone has dissolved. The temperature is main 4-(Trifluoromethyl)-a-phenyl-0-toluidine tained between 120°-1 50 C. for 45 minutes until gas evolution ceases. After a total heating period of 1.5 65 In the manner given in Preparation 1 1, 2-amino-5- hours, the solution is cooled, poured on to ice and ex (trifluoromethyl)benzophenone is refluxed with potas tracted with benzene. The benzene layer is separated, sium hydroxide in diethylene glycol to give 4-(tri dried over anhydrous magnesium sulfate and concen fluoromethyl)-a-phenyl-0-toluidine.

3,941,802 9 10 g (0.795 mol) of amino acetaldehyde, dimethylacetal. Preparation 20 The solution is stirred at room temperature for 20 min 2-Benzyl-4-nitroaniline utes and then refluxed for 3% hours. C. The solvent is removed in vacuo and the resulting in the manner given in Preparation l 1, 2-amino-5- oil, dissolved in 1 l. of monoglyme, is treated cautiously nitrobenzophenone hydrazone is refluxed with potas with 34.9 ml. (60.4 g., 0.318 mol) of reagent titanium sium hydroxide in diethylene glycol to give 2-benzyl-4- tetrachloride. The reaction mixture is stirred at ambi nitroaniline. ent temperature for 10 minutes, then refluxed for 4 In the manner given in the preceding preparations hours, cooled to room temperature, poured on to ice other a-phenyl-0-toluidine can be synthesized. Repre O and neutralized with 5.0 l. of cold 10% aqueous sodium sentative compounds thus obtained include: hydroxide solution. The mixture is treated with chloro 2-(0-chlorobenzyl)-4-bromoaniline; form and both layers are filtered through Celite to 4-chloro-a-(m-chlorophenyl)-0-toluidine; remove suspended solids. The layers are separated and 5-bromo-o-(0-fluorophenyl)-0-toluidine; the aqueous layer is extracted thoroughly with methy 4-bromo-a-phenyl-0-toluidine; S lene chloride. The combined organic layers are washed 3-fluoro-a-(0-fluorophenyl)-0-toluidine; with brine, dried over anhydrous magnesium sulfate 3-(trifluoromethyl)-a-phenyl-0-toluidine; and concentrated in vacuo to an oil (140.0 g) which is 5-nitro-a-0-(trifluoromethyl)phenyl)-0-toluidine; chromatographed over 4.8 kg. of silica gel by eluting a-(0-fluorophenyl)-0-toluidine; with 30% ethyl acetate/70% Skellysolve B hexane mix 4-bromo-a-(0-chlorophenyl)-0-toluidine; 20 tures and taking 600 ml. fractions. After the 20th frac and the like. tion the column is eluted with a 50% ethyl acetate/Skel EXAMPLE lysolve B hexane mixture. The product is isolated in fractions 21-29 and crystallized from ethyl acetate to 1-(4-Chloro-a-phenyl-0-tolyl)imidazole afford 18.43 g of 1-(4-chloro-a-(0-chlorophenyl)-0- A. A solution of 50.6 g. (0.233 mmol) of 2-benzyl-4- 25 tolyl)imidazole of melting point 62-63 C. An analyti chloroaniline and 82.85 g. (0.5095 mole of triethyl cal sample has a melting point 63.5°-64.5°C. orthoformate are kept at reflux during 5 hours. About Anal. calcd. for CHClN2, mw 303, 19: C, 63.38; 75 ml. of ethanol and other low boiling material are H, 3.99; N, 9.24; Cl, 23.39. Found: C, 63.15; H, 3.94; distilled leaving an oily residue. N, 9.19; C1, 23.18. B. The residual oil is then cooled to room tempera 30 ture, dissolved in 500 ml. of reagent methanol and EXAMPLE 3 treated with 83.5 (0.795 mol) of aminoacetaldehyde, 5-Methyl-1-(4-chloro-a-phenyl-0-tolyl)imidazole dimethyl acetal, The solution is refluxed for 3 hours A. N'-(4-Chloro-a-phenyl-0-tolyl)-N-(2-methyl until the iminoether has reacted completely, 1,3-dioxolan-2-yl)methyl)formalidine C. The solvent is then removed in vacuo to give an oil A solution of 5.06 g. (23.3 mmol) of 2-benzyl-4- which is dissolved in 1 liter of monoglyme. To this chloroaniline and 8.28 g. (51.0 mol) of triethyl ortho solution is carefully added 34.9 ml. of titanium tetra formate is refluxed for 5 hours to distill ethanol. The chloride (60.4 g., 0.318 mol). The solution turns brown resulting yellow oil is dissolved in 25 ml. of absolute immediately and warms considerably during the addi 40 ethanol, treated with 2-methyl-2-(aminomethyl)-1,3- tion of the metal salt. The reaction mixture is stirred at dioxolane and heated for 1.5 hours at reflux. All the ambient temperature for 10 minutes, then refluxed for volatile liquids are removed in vacuo to afford 5.26 g. 4 hours. It is permitted to cool overnight, then neutral of N'-(4-chloro-a-phenyl-0-tolyl)-N-(2-methyl-1,3- ized by pouring into 5.0 liter of cold aqueous 5% so dioxolan-2-yl)methyl)formalidine which is filtered and dium hydroxide solution and extracting with chloro 45 washed with hexane. The analytical sample recrystal form (approximately 9 liter of solvent are used). The lized from ethyl acetate/hexane has a melting point of organic layers are washed with saturated aqueous so 05°-107 C. dium chloride, dried over anhydrous magnesium sul Anal. calcd. for CHCINO, mw 344.83: C, 66.17; fate and concentrated to a syrup to give 51.6 g. of a H, 6.4; N, 8.13; Cl, 10.28; Found: C, 65.98; H, 6.12; black tarry substance. This is chromatographed over 50 N, 8.03; C1, 10.35. 2500 g. of silica gel and eluted with ethyl acetate, tak B. 5-Methyl-1-(4-chloro-a-phenyl-0-tolyl)imidazole ing 1 liter fractions. The product is isolated in fractions The product from A (2.77 g., 8.11 mol) is dissolved 8 to 14 to give, after recrystallization from ether/hex in 40 ml. of monoglyme and treated carefully at room ane, 29.77 g. (48%) of colorless prisms of 1-(4-chloro temperature with 1.22 ml. (2.10 g., 11.1 mmol) of a-phenyl-0-tolyl)imidazole of melting point 69-70.5 55 reagent titanium tetrachloride. After the initial vigor C. ous exothermic reaction has subsided, the reaction Anal. calcd. for CHClN; mw. 268.73: C, 71.5; mixture is heated to reflux on a steam bath for 3 hours. H, 4.87; N, 10.43; C1, 13.19. Found: C, 71.81; H, 4.82; The reaction mixture is quenched on ice, neutralized, N, 10.42; C1, 13.31. extracted with , dried and chromatographed EXAMPLE 2 SO over 150 g of silica gel by eluting with 100 ml. of ethyl acetate and 900 ml. of a 1/99 methanol/ethyl acetate 1-4-Chloro-a-(0-chlorophenyl)0-toly-imidazole mixture (18 ml. fractions are collected). The product is A. 4-chloro-a-(0-chlorophenyl)-0-toluidine (58.7 g., collected in fractions 24-37 and crystallized from ethyl 0.233 mol) is refluxed for 3 hours with 83.0 g (0.509 acetate/hexane mixtures to afford 0.71 g of 5-methyl mol) of triethyl orthoformate to remove ethanol leav 1-(4-chloro-a-phenyl-0-tolyl)imidazole of melting ing an oily residue. point 64-66' C. A second crop weighs 0.17 g. The B. This oily residue is cooled to room temperature, analytical sample, crystallized from ethyl acetate/hex dissolved in 500 ml, of methanol and treated with 83.5 ane mixtures, has a melting point of 65-66 C. 3,941,802 11 12 Anal. calcd. for CHCN, mw 282.76: C, 72.21; H, 5.35; N, 9.9; C1, 12.54. Found: C, 71.97; H, 5.38; N, EXAMPLE O 9.79; C1, 2.85. 1-4-Chloro-a-(2,6-difluorophenyl)-0-tolyl)imidazole EXAMPLE 4 In the manner given in Example 1, 4-chloro-a-(2,6- 5 difluorophenyl)-0-toluidine is reacted first with tri l-4-Nitro-a-(0-chlorophenyl)-0-tolyl)imidazole methyl orthoformate; the resulting product is reacted In the manner given in Example 1, 4-nitro-o-(0- with aminoacetaldehyde, dimethyl acetal, and the re chlorophenyl)-0-toluidine is reacted first with trimethyl sulting product of this reaction is heated with titanium orthoformate; the resulting product is reacted with O tetrachloride in monoglyme to give I-4-chloro-a-(2,6- aminoacetaldehyde, dimethyl acetal, and the resulting difluorophenyl)-0-tolyl)imidazole. product of this reaction is heated with titanium tetra EXAMPLE chloride in monoglyme to give 1-4-nitro-a-(0-chloro phenyl)-0-tolyl)imidazole. 4-Ethyl-5-methyl-1-(4-chloro-a-(2,6-difluorophenyl)- 15 0-tolyl)imidazole EXAMPLE 5 In the manner given in Example 3, 4-chloro-a-(2,6- 5-Methyl-l-4-nitro-a-(0-chlorophenyl)-0-tolyl difluorophenyl)-0-toluidine is reacted with triethylor imidazole thoformate, the resulting oil is heated with 2-methyl-2- In the manner given in Example 3, 4-nitro-a-(0- (-aminopropyl)-1,3-dioxolane, and the resulting prod chlorophenyl)-0-toluidine is reacted with triethyl or uct is treated with titanium tetrachloride to give 4 thoformate. The resulting oil is heated with 2-methyl-2- ethyl-5-methyl-1-(4-chloro-a-(2,6-difluorophenyl)-0- (aminomethyl)-1,3-dioxolane, and the resulting prod tolyl)imidazole. uct treated with titanium tetrachloride to give 5-meth EXAMPLE 12 yl-l-4-nitro-a-(0-chlorophenyl)-0-tolyl)imidazole. 25 1-(4-Nitro-a-phenyl-0-tolyl)imidazole EXAMPLE 6 In the manner given in Example 1, 4-nitro-a-phenyl 1-4-Fluoro-a-(0-chlorophenyl)-0-tolyl)imidazole 0-toluidine is reacted first with trimethyl orthoformate; In the manner given in Example 1, 4-fluoro-o-(0- the resulting product is reacted with aminoacetalde chlorophenyl)-0-toluidine is reacted first with trimethyl hyde, dimethyl acetal, and the resulting product of this orthoformate; the resulting product is reacted with reaction is heated with titanium tetrachloride in mono aminoacetaldehyde, dimethyl acetal, and the resulting glyme to give 1-4-nitro-a-phenyl-0-tolyl)imidazole. product of this reaction is heated with titanium tetra EXAMPLE 13 chloride in monoglyme to give l-4-fluoro-a-(0-chloro 5-Methyl-1-(4-nitro-a-phenyl-0-tolyl)imidazole phenyl)-0-tolyl)imidazole. 35 In the manner given in Example 3, 4-nitro-a-phenyl EXAMPLE 7 0-toluidine is reacted with triethyl orthoformate, the 5-Ethyl-1-(4-fluoro-a-(0-chlorophenyl)-0-tolyl resulting oil is heated with 2-methyl-2-(aminomethyl)- imidazol 1,3-dioxolane, and the resulting product treated with 40 titanium tetrachloride to give 5-methyl-1-(4-nitro-a- In the manner given in Example 3, 4-fluoro-a-(0- phenyl-0-tolyl)imidazole. chlorophenyl)-0-toluidine is reacted with triethyl or thoformate, the resulting oil is heated with 2-ethyl-2- EXAMPLE 4 (aminomethyl)-1,3-dioxolane, and the resulting prod 1-(4-Fluoro-a-phenyl-0-tolyl)imidazole uct is treated with titanium tetrachloride to give 5 45 In the manner given in Example 1,4-fluoro-a-phenyl ethyl-l-4-fluoro-a-(0-chlorophenyl)-0-tolyl 0-toluidine is reacted first with trimethyl orthoformate; imidazole. the resulting product is reacted with aminoacetalde EXAMPLE 8 hyde, dimethyl acetal, and the resulting product of this reaction is heated with titanium tetrachloride in mono 1-4-(Trifluoromethyl)-a-phenyl-0-tolyl)imidazole SO glyme to give 1-(4-fluoro-a-phenyl-0-tolyl)imidazole. In the manner given in Example 1, 4-(trifluorome thyl)-a-phenyl-0-toluidine is reacted first with tri EXAMPLE 15 methyl orthoformate; the resulting product is reacted 5-Methyl-1-(4-chloro-a-(0-chlorophenyl)-0-tolyl )imidazole with aminoacetaldehyde, dimethyl acetal, and the re 55 sulting product of this reaction is heated with titanium In the manner given in Example 3, 4-chloro-a-(0- tetrachloride in monoglyme to give 1-(4-trifluorome chloro-phenyl)-0-toluidine is reacted with triethyl or thyl)-a-phenyl-0-tolyl)imidazole. thoformate, the resulting oil is heated with 2-methyl-2- EXAMPLE 9 (aminomethyl)-1,3-dioxolane, and the resulting prod 60 uct treated with titanium tetrachloride to give 5-meth 5-Methyl-1-(4-(trifluoromethyl)-a-phenyl-0-tolyl yl-1-(4-chloro-a-(0-chlorophenyl)-0-tolyl)imidazole. imidazole EXAMPLE 6 in the manner given in Example 3, 4-(trifluorome thyl)-a-phenyl-0-toluidine is reacted with triethyl or 1-(a-Phenyl-0-tolyl)imidazole thoformate, the resulting oil is heated with 2-methyl-2- 65 In the manner given in Example l, a-phenyl-0-tolui (aminomethyl)-1,3-dioxolane, and the resulting prod dine is reacted first with trimethyl orthoformate; the uct treated with titanium tetrachloride to give 5-meth resulting product is reacted with aminoacetaldehyde, yl-1-(4-trifluoromethyl)-0-phenyl-0-tolyl)imidazole. dimethyl acetal, and the resulting product of this reac 3,941,802 13 14 tion is heated with titanium tetrachloride in mono thoformate, the resulting oil is heated with 2-propyl-2- glyme to give 1-(a-phenyl-0-tolyl)imidazole. (aminomethyl)-1,3-dioxolane, and the resulting prod uct treated with titanium tetrachloride to give 5-propyl EXAMPLE 7 1-4-bromo-a-(0-chlorophenyl)-0-tolyl)imidazole. 5-Methyl-1-(a-phenyl-0-tolyl)imidazole In the manner given in the preceding examples other 1-(a-phenyl-0-tolyl)imidazoles IV can be obtained. In the manner given in Example 3, a-phenyl-0-tolui Representative compounds thus obtained include: dine is reacted with triethyl orthoformate, the resulting 1-(4-bromo-a-phenyl-0-tolyl)imidazole; oil is heated with 2-methyl-2-(aminomethyl)-1,3-diox 1-(5-bromo-a-phenyl-0-tolyl)imidazole; olane, and the resulting product treated with titanium O 4-methyl-1-(5-bromo-a-phenyl-0-tolyl)imidazole; tetrachloride to give 5-methyl-1-(a-phenyl-0-tolyl 5-methyl-1-(5-bromo-a-phenyl-0-tolyl)imidazole; )imidazole. 4,5-dimethyl-1-(5-bromo-a-phenyl-0-tolyl EXAMPLE 8 )imidazole, 4-methyl-1-(a-(m-chlorophenyl)-0-tolyl)imidazole; 1-(4-chloro-a-(0-fluorophenyl)-0-tolyl)imidazole 15 4-propyl-1-(a-(m-chlorophenyl)-0-tolyl)imidazole; In the manner given in Example 1, 4-chloro-a-(0- 5-ethyl-4-propyl-1-(a-(m-chlorophenyl)-0-tolyl fluorophenyl)-0-toluidine is reacted first with trimethyl imidazole; orthoformate; the resulting product is reacted with 4,5-dimethyl-1-(4-(trifluoromethyl)-a-(0-chloro aminoacetaldehyde, dimethyl acetal, and the resulting phenyl)0-tolyl)imidazole; product of this reaction is heated with titanium tetra 4,5-diethyl-1-(4-nitro-a-(0-chlorophenyl)-0-tolyl chloride in monoglyme to give 1-(4-chloro-a-(0-fluoro imidazole; phenyl)-0-tolyl)imidazole. 5-propyl-1-(4-chloro-a-phenyl-0-tolyl)imidazole; EXAMPLE 9 and the like. 5-Methyl-1-(a-(0-chlorophenyl)-0-tolyl)imidazole 25 EXAMPLE 24 in the manner given in Example 3, at-(0-chloro 5-Chloro-2-(imidazol-1-yl)benzophenone phenyl)-0-toluidine is reacted with triethyl orthofor In a 500 ml. round bottom flask, 26.8 g. (0.100 mol) mate, the resulting oil is heated with 2-methyl-2- of 1-(4-chloro-a-phenyl-0-tolyl)imidazole is dissolved (aminomethyl)-1,3-dioxolane, and the resulting prod in 100 ml. of acetic acid. One hundred ml. of Jones' uct treated with titanium tetrachloride to give 5-meth 30 reagent is carefully added and the mixture is refluxed yl-1-(o-(0-chlorophenyl)-0-tolyl)imidazole. under nitrogen for 4 hours on a steam bath. After cool ing to room temperature, the mixture is poured into 4.0 EXAMPLE 2.0 liter of cold 7% aqueous sodium hydroxide solution and 1-a-(0-chlorophenyl)-0-tolyl)imidazole extracted with 2.2 liter of chloroform. The chloroform In the manner given in Example 1, a-(0-chloro extract is washed with aqueous saturated sodium chlo phenyl)-0-toluidine is reacted first with trimethyl or ride, dried over anhydrous magnesium sulfate, filtered, thoformate; the resulting product is reacted with and concentrated to give a dark oil. This oil is dissolved aminoacetaldehyde, dimethyl acetal, and the resulting in ethyl acetate, treated with 1.0 g of activated char product of this reaction is heated with titanium tetra 40 coal, and filtered through anhydrous magnesium sul chloride in monoglyme to give 1-a-(0-chlorophenyl)- fate. Crystallization from ethyl acetate?hexane (%) 0-tolyl)imidazole. affords 15.3 g of 5-chloro-2-(imidazol-1-yl)benzophe none. Recrystallization of 1.0 g of the product from EXAMPLE 21 ethyl acetate affords 0.30 g. of colorless prisms, of 4,5-Diethyl-1-(a-(0-fluorophenyl)-0-tolyl)imidazole 45 melting point 106-108 C. in the manner given in Example 3, at-(0-fluoro Anal. for for CHCINO: C, 67.97; H, 3.92; N, phenyl)-0-toluidine is reacted with triethyl orthofor 9.91; C, 12.54. Found: C, 67.78, H, 3.94; N, 9.97; Cl, mate, the resulting oil is heated with 2-ethyl-2-(1- 12.57. aminopropyl)-1,3-dioxolane, and the resulting product EXAMPLE 25 treated with titanium tetrachloride to give 4,5-diethyl SO |-a-(0-fluorophenyl)-0-tolyl)imidazole. 2,5-Dichloro-2-(imidazol-1-yl)benzophenone In a 500 ml. round bottom flask 30.3 g (0.100 mol) EXAMPLE 22 of 1-(4-chloro-a-(0-chlorophenyl)-0-tolyl)imidazole is 1-4-Bromo-a-(0-chlorophenyl)-0-tolyl)imidazole dissolved in 100 ml. of acetic acid. One hundred ml. of 55 Jones' reagent is added carefully and the mixture is In the manner given in Example 1, 4-bromo-o-(0- refluxed under nitrogen for 4 hours on a steam bath. chlorophenyl)-0-toluidine is reacted first with trime After cooling to room temperature, the mixture is thylorthoformate; the resulting product is reacted with poured into 4.0 l. of cold aqueous 7% sodium hydrox aminoacetaldehyde, dimethyl acetal and the resulting ide solution and extracted with 2.2 l. of chloroform. product of this reaction is heated with titanium tetra 60 The chloroform extract is washed with an aqueous chloride in monoglyme to give 1-(4-bromo-o'-(0- saturated sodium chloride solution, dried over anhy chlorophenyl)-0-tolyl)imidazole. drous magnesium sulfate and concentrated to an oil EXAMPLE 23 which crystallizes from ethyl acetate to afford 2',5- dichloro-2-(imidazol-1-yl)benzophenone of melting 5-Propyl-1-(4-bromo-a-(0-chlorophenyl-0-tolyl 65 point 146-148 C. imidazole Anal. calcd. for CHClNO, mw 37.7: C, 60.59; In the manner given in Example 3, 4-bromo-a-(0- H, 3.18; N, 8.83; C1, 22.36. Found: C, 60:96; H, 3.38; chlorophenyl)-0-toluidine is reacted with triethyl or N, 8.97, Cl, 22.26. 3,941,802 16 EXAMPLE 26 EXAMPLE 34 5-Chloro-2-(5-methylimidazol-1-yl)benzophenone 5-Chloro-2',6'-difluoro-2-(imidazo-1-yl)benzophe Oe In the manner described in example 24, 5-methyl-1- 5 (4-chloro-a-phenyl-0-tolyl)imidazole in acetic acid is In the manner given in Example 24, 1-(4-chloro-a- treated with Jones' reagent and heated for 3 hours on a (2,6-difluorophenyl)-0-tolyl)imidazole in acetic acid is steam bath to give 5-chloro-2-(5-methylimidazol-1- heated with Jones' reagent to give 5-chloro-2',6'- yl)benzophenone. difluoro-2-(imidazo-1-yl)benzophenone. O EXAMPLE 27 EXAMPLE 35 5-Chloro-2',6'-difluoro-2-(4-ethyl-5-methylimidazo-1- 2,5-Dichloro-2-(5-methylimidazol-1-yl)benzophe yl)benzophenone One In the manner given in Example 24, 4-ethyl-5-meth In the manner given in Example 24, 5-methyl-1-(4- 15 yl-1-(4-chloro-a-(2,6-difluorophenyl)-0-tolyl chloro-a-(0-chlorophenyl)-0-tolyl)imidazole in acetic imidazole in acetic acid is heated with Jones'reagent acid is heated with Jones' reagent to give 2",5-dichloro to give 5-chloro-2',6'-difluoro-2-(4-ethyl-5- 2-(5-methylimidazo-l-yl)benzophenone. methylimidazo-1-yl)benzophenone. EXAMPLE 28 20 EXAMPLE 36 2'-Chloro-5-nitro-2-(imidazo-1-yl)benzophenone 5-Nitro-2-(imidazo-1-yl)benzophenone In the manner given in Example 24, 1-4-nitro-a-(0- In the manner given in Example 24, 1-(4-nitro-a-phe chlorophenyl)-0-tolyl)imidazole in acetic acid is nyl-0-tolyl)imidazole in acetic acid is heated with heated with Jones' reagent to give 2'-chloro-5-nitro-2- Jones' reagent to give 5-nitro-2-(imidazo-1-yl)ben (imidazo-1-yl)benzophenone. 25 zophenone. EXAMPLE 29 37 2'-Chloro-5-nitro-2-(5-methylimidazo-1-yl)benzophe 37-5-Nitro-2-(5-methylimidazo-1-yl)benzophenone One 30 In the manner given in Example 24, 5-methyl-1-(4- ln the manner given in Example 24, 5-methyl-l-4- nitro-a-phenyl-0-tolyl)imidazole in acetic acid is nitro-a-(0-chlorophenyl)-0-tolyl)imidazole in acetic heated with Jones' reagent to give 5-nitro-2-(5- acid is heated with Jones' reagent to give 2'-chloro-5- methylimidazo-1-yl)benzophenone. nitro-2-(5-methylimidazo-1-yl)benzophenone. 35 EXAMPLE 38 EXAMPLE 30 5-Fluoro-2-(imidazo-1-yl)benzophenone 2'-Chloro-5-fluoro-2-(imidazo-1-yl)benzophenone In the manner given in Example 24, 1-(4-fluoro-a- In the manner given in Example 24, 1-4-fluoro-o-(0- phenyl-0-tolyl)imidazole in acetic acid is heated with chlorophenyl)-0-tolyl)imidazole in acetic acid is 40 Jones' reagent to give 5-fluoro-2-(imidazo-1-yl)ben heated with Jones' reagent to give 2'-chloro-5-fluoro-2- zophenone. (imidazo-1-yl)benzophenone. EXAMPLE 39 EXAMPLE 3 2'-Chloro-2-(imidazo-1-yl)benzophenone 2'-Chloro-5-fluoro-2-(5-ethylimidazo-1-yl)benzophe 45 In the manner given in Example 24, 1-a-(0-chloro O phenyl)-0-tolyl)imidazole in acetic acid is heated with In the manner given in Example 24, 5-ethyl-1-(4- Jones' reagent to give 2'-chloro-2-(imidazo-1-yl)ben fluoro-a-(0-chlorophenyl)-0-tolyl)imidazole in acetic zophenone. acid is heated with Jones' reagent to give 2'-chloro-5- 50 EXAMPLE 40 fluoro-2-(5-ethylimidazo-1-yl)benzophenone. 2-(5-Methylimidazo-1-yl)benzophenone EXAMPLE 32 In the manner given in Example 24, 5-methyl-1-(a- 5-(Trifluoromethyl)-2-(imidazo-1-yl)benzophenone phenyl-0-tolyl)imidazole in acetic acid is heated with Jones' reagent to give 2-(5-methylimidazo-1-yl)ben In the manner given in Example 24, -(4-(tri 55 zophenone. fluoromethyl)-a-phenyl-0-tolyl)imidazole in acetic acid is heated with Jones' reagent to give 5-(tri EXAMPLE 4 fluoromethyl)-2-imidazo-i-yl)benzophenone. 2'-Chloro-2-(5-methylimidazo-1-yl)benzophenone EXAMPLE 33 60 In the manner given in Example 24, 5-methyl-l-a- (0-chlorophenyl)-0-tolyl)imidazole in acetic acid is 5-(Trifluoromethyl)-2-(5-methylimidazo-i-yl)ben heated with Jones' reagent to give 2'-chloro-2-(5- zophenone methylimidazo-1-yl)benzophenone. In the manner given in Example 24, 5-methyl-1-(4- In the manner given in Example 24, other 2 (trifluoromethyl)-a-(0-chlorophenyl)-0-tolyl 65 (imidazol-1-yl)benzophenones can be produced. Rep imidazole in acetic acid is heated with Jones' reagent resentative products thus obtained include: to give 5-(trifluoromethyl)-2-(5-methylimidazo-1- 5-chloro-2'-fluoro-2-(imidazol-1-yl)benzophenone; yl)benzophenone. 5-bromo-2'-chloro-2-(imidazol-1-yl)benzophenone; 3,941,802 17 18 2'-chloro-5-fluoro-2-(imidazol-1-yl)benzophenone; 4-chloro-2-(imidazol-1-yl)benzophenone; wherein R' and R" are hydrogen, methyl, or ethyl; 3-(trifluoromethyl)-2-(imidazol-1-yl)benzophenone; wherein R', is hydrogen, chloro or fluoro; wherein R's 3'-chloro-2-(imidazol-l-yl)benzophenone; is hydrogen or fluoro with the proviso that R's is not 5,4'-dichloro-2-(imidazol-1-yl)benzophenone; fluoro, if R", is chloro; and wherein R' is hydrogen, 5-bromo-2'-chloro-2-(5-methylimidazol-1-yl)ben fluoro, chloro, or trifluoromethyl. Zophenone; 3. A compound according to claim 1 of the formula 5-chloro-2'-fluoro-2-(5-methylimidazol-1-yl)ben VB: Zophenone; 5-nitro-2'-fluoro-2-(5-ethylimidazol-1-yl)benzophe O 5-nitro-2-(5-propylimidazol-1-yl)benzophenone;none, 5-fluoro-2-(5-isopropylimidazol-1-yl)benzophenone; 5-(trifluoromethyl)-2-(4,5-dimethylimidazol-1- yl)benzophenone; 5 4-bromo-2'-chloro-2-(4,5-diethylimidazol-1-yl)ben zophenone; 5-fluoro-2'-chloro-2-(4,5-dipropylimidazol-1-yl)ben R". Zophenone; 20 and the like. I claim: 1. A compound of the formula V:

25

wherein R' is hydrogen or methyl; wherein R', is 30 hydrogen or chloro; wherein R' is hydrogen, chloro or fluoro. 4. A compound according to claim 3, wherein R' and R', are hydrogen, R' is chloro and the compound is therefore 5-chloro-2-(imidazol-1-yl)benzophenone. 35 5. A compound according to claim 3, wherein R' is hydrogen, R', and R', are chloro and the compound is therefore 2',5-dichloro-2-(imidazol-1-yl)benzophe O. 6. A compound according to claim 3, wherein R' is 40 methyl, R', is hydrogen, R' is chloro and the com pound is therefore 5-chloro-2-(5-methylimidazol-1- wherein Ro and R are hydrogen or alkyl of 1 to 3 car yl)benzophenone. bon atoms, inclusive; wherein R is hydrogen, fluoro, 7. A compound according to claim 3, wherein R' chloro, or trifluoromethyl; wherein Ra is hydrogen or and R', are hydrogen, R', is chloro and the compound fluoro with the proviso that R is not fluoro, if R is 45 is therefore 2'-chloro-2-(imidazol-1-yl)benzophenone. chloro or trifluoromethyl; and wherein R is hydrogen, 8. A compound according to claim 3, wherein R' fluoro, chloro, bromo, trifluoromethyl, or nitro. and R', are hydrogen, R' is fluoro and the compound 2. A compound according to claim 1 of the formula is therefore 5-fluoro-2-(imidazol-1-yl)benzophenone. VA: 9. A compound according to claim 3, wherein R' is 50 methyl, R', and R', are chloro and the compound is therefore 2,5-dichloro-2-(5-methylimidazol-1-yl)ben Ro zophenone. 10. A compound according to claim 2, wherein R' is R 21 methyl, R'o, R', and R's are hydrogen, R", is trifluoro 55 methyl and the compound is therefore 5-(trifluorome thyl)-2-(5-methylimidazol-1-yl)benzophenone. 11. A compound according to claim 2, wherein R', N-(H R", and R's are hydrogen, R", is fluoro, R", is chloro, WA and the compound is therefore 5-chloro-2'-fluoro-2- R O 60 imidazol-1-yl)benzophenone. 12. A compound according to claim 1, wherein Ro, R R2 R, and Ra are hydrogen, R is methyl, R is 5-nitro and the compound is therefore 5-nitro-2-(5- methylimidazol-1-yl)benzophenone. 65 ck k ck k k