HU180088B - Process for producing n-trityl-imidasole derivatives - Google Patents

Abstract

: The specification discloses a process for preparing n-tritylimidazole compounds of the formula: ¢I! <IMG> by the reaction between a tritylcarbinol derivative of the formula: ¢II! <IMG> and a tri(l-imidazolyl)phosphine derivative of the formula: <IMG> ¢III! This process provides a more convenient and economic route to these known compounds than the processes conventionally used.

Description

The present invention relates to a novel process for the preparation of N-tritylimidazole derivatives. More particularly, the present invention relates to an improved process for the preparation of N-tritylimidazole derivatives of formula I wherein X ₁ , X ₂ and X _{3 are} hydrogen or one of them represents halogen and the remaining two groups are hydrogen.

The N-tritylimidazole derivatives of formula I are valuable antifungal and antibacterial agents (U.S. Patent Nos. 3,321,366 and 3,705,172).

The N-tritylimidazole compounds of formula (I) are prepared by reacting the halides or salts of the corresponding tritylcarbinol derivatives with the silver or sodium salt of the corresponding imidazole compound according to the cited US patents. The disadvantage of this method is that the tritylcarbinol halides and salts are water-labile compounds and thus difficult to prepare; the imidazole silver salt is a costly and photo-degradable compound; furthermore, the desired end products can be obtained by this process only in low yield.

The N-tritylimidazole derivatives of formula (I) may also be prepared by reaction of the corresponding tritylcarbinol compounds with imidazole. Although this process does not require expensive and unstable starting materials, it is a serious drawback that the desired end products can be formed only at low yields, even at very high temperatures for extended periods of time. Thus, this method is not suitable for the large-scale commercial production of Ntritylimidazole compounds of formula (I).

In our attempts to simplify and economize the preparation of N-trityl imidazole derivatives, it has been found that these compounds can be prepared simply, under mild conditions and in high yields, by treating the corresponding tritylcarbinol derivatives with tri- (1-imidazolyl). reaction with phosphine. It has also been found that o-chlorophenyldiphenylmethanol, a starting material for the preparation of a very potent antifungal agent known as Clotrimazole of the formula I, can be obtained in very good yields such that the o-chlorobenzotri and benzene in the presence of aluminum chloride are treated with water.

The present invention therefore relates to a process for the preparation of N-tritylimidazole derivatives of formula (I). According to the invention, the tritylcarbinol derivatives of formula II, wherein X ₁ , X ₂ and X ₃ are as defined above, are optionally reacted with tri-l-imidazolylphosphine of formula III, optionally in situ.

The process of the invention is a preferred fo180088 1

1-1180,088, 1- [2-chlorophenyl) diphenylmethyl] imidazole is prepared by treating the reaction mixture formed by the reaction of o-chlorobenzotrichloride and benzene with aluminum chloride, and the resulting o-chloro is obtained. -phenyldiphenylmethanol is reacted with tri- (1-imidazolyl) phosphine.

The reaction of the compounds of formula (H) »and III is generally carried out at a temperature of about -5 ° C to + 130 ° C, preferably at about 0 ° C to about 100 ° C, in the presence of a suitable solvent.

Generally, more than 1/3 mol of tri- (1-imidazolyl) phosphine of formula (III) is used per mole of tritylcarbinol derivative (II). Good results are obtained when 2 - 3 to 3 mol of tri-l-imidazolylphosphine (III) are added to 1 mol of tritylcarbinol derivative (II).

Suitable solvents for the process include aromatic hydrocarbons such as benzene or toluene, halogenated aliphatic hydrocarbons such as chloroform or dichloromethane, and tetrahydrofuran, methyl isobutyl ketone, dimethylformamide, Ideine, acetonitrile, or mixtures thereof.

The tritylcarbinol derivatives of formula (II) and the tri (1-imidazolyl) phosphine of formula (III) used as starting materials in the process of the invention are known compounds and can be prepared by known methods (J. Org. Chem. 7, 392 (1942)). Chem. Soc. 33, 3331 (1911),

Angew. Chem. 73, 143 (1961).

The tri- (1-imidazolyl) phosphine of formula (III) may also be prepared by reacting phosphorus trichloride in an imidazole solvent medium of formula (IV) in the presence of an acid acceptor.

The tri-l-imidazolylphosphine (III) is a moisture sensitive substance; therefore, the compound is preferably reacted in isolation with the tritylcarbinol derivatives of formula (II) without isolation.

The following examples illustrate the invention without limiting it.

Example 1 Preparation of o-Chloro-phenyl-diphenyl-methanol A suspension of 138 g (0.6 mol) of o-chlorobenzotrichloride in 145 ml of benzene was added dropwise over 2 hours at 60 ° C to a suspension of aluminum chloride in 380 ml of benzene. After the addition, the reaction mixture was refluxed for 2 hours. The reaction mixture was poured into water (600 ml) and the flask was washed with benzene (240 ml) and water (120 ml). The resulting mixture was refluxed for 4 hours. The organic layer was separated, washed with water (400 mL), clarified with charcoal (6 g) and filtered. Concentration of the benzene filtrate gave 172.6 g (97.7%) of o-chlorophenyldiphenylmethanol as a crystalline residue; mp 88.5-91.5 ° C.

A sample of 80 g of the crude o-chloro-femyl-difemyl-methanol obtained is recrystallized from isopropanol. 71 g of pure product are obtained; mp 92-94 ° C.

Analysis: Calculated: C, 77.41; H, 5.13; Cl, 12.03; Found: C, 77.58; H, 5.01; Cl, 12.30.

Example 2 Preparation of 1- (o-Chlorophenyl-diphenylmethyl) -imidazole

In a solution of 0.99 g (4.3 mmol) of tri- (1-imidazolyl) phosphine in 30 ml of chloroform at 0 - 10 ° C was added 2.50 g (8.5 mmol) of pure o-chlorophenyldiphenyl- methanol solution was added dropwise. Water was added and the reaction mixture was extracted with chloroform. The extract was washed with 5% aqueous sodium hydroxide solution, then water, dried over magnesium sulfate and finally concentrated. The residue was recrystallized from acetonitrile. 2.2 g (75 °) of 1- (o-chlorophenyldiphenylmethyl) imidazole are obtained; mp 142-143 ° C.

Analysis calculated for C ₂₂ H ₁₇ N ₂ Cl: C, 76.64; N, 8.12; H, 4.97; Found: C, 76.53; N, 8.41; H, 4.65.

Example 3 Preparation of 1- (o-Chloro-phenyl-diphenylmethyl) -imidazole

To a solution of 122.4 g (1.8 mol) of imidazole and 181.8 g (1.8 mol) of triethylamine in 1200 ml of chloroform is added dropwise 88.2 g (0.6 mol) of phosphorus trichloride at 0 to 10 ° C. . After stirring for 1 hour, the resulting solution was treated with crude o-chlorophenyldiphenylmethanol (172 g), and the reaction mixture was refluxed for 1 hour. The reaction mixture was cooled, stirred with water and extracted with chloroform. The extract was washed with water, 10% aqueous potassium carbonate solution and finally water, dried over magnesium sulfate, clarified with 18 g of charcoal, filtered and the filtrate was evaporated. The resulting 240 g of an oily residue is crystallized from 130 ml of acetonitrile. 159 g (77.1%) of 1- (O-chlorophenyldiphenylmethyl) imidazole are obtained; mp 142-143 "C. This crude product was recrystallized from 330 mL of acetonitrile to give 144.2 g (69%) of pure 1- (o-chlorophenyl-diphenylmethyl) -1-imidazole; mp 143-144 ° C.

Example 4 Preparation of 1- (o-chlorophenyldiphenylmethyl) imidazole

To a solution of imidazole (2.24 g, 33 mol) and triethylamine (3.03 g, 33 mmol) in chloroform (40 ml) was added dropwise 1.51 g (11 mmol) of phosphorus trichloride at 5-15 ° C and the mixture was stirred for 1 hour. To the resulting solution was added 2.95 (0.01 mol) of purified o-chlorophenyldiphenylmethanol and the mixture was refluxed for 2 hours. The reaction mixture was worked up as described in Example 3. 3.10 g (90%) of 1- (o-chlorophenyldiphenylmethyl) imidazole are obtained; mp 140-142 ° C.

Example 5 Preparation of 1- (o-Chloro-phenyl-diphenylmethyl) -imidazole

2.24 g (33 mmol) of imidazole and 3.03 (33 mmol) of triethylamine in 40 mL of toluene

-2183,088

At 50-55 ° C, 1.51 g (11 mmol) of phosphorus trichloride are added dropwise and the reaction mixture is stirred for 1 hour. Purified o-chlorophenyldiphenylmethanol (2.95 g, 0.01 mol) was added to the reaction mixture and refluxed for 2 hours. The mixture was cooled, water (40-50 ml) was added and the organic layer was separated. Wash with 5% aqueous potassium carbonate solution and water, dry over magnesium sulfate and finally evaporate. The residue was crystallized from acetonitrile. 2.78 g (80%) of 1- (o-chlorophenyldiphenylmethyl) imidazole are obtained; mp 142-143 ° C.

Example 6 Preparation of 1- (o-Chloro-phenyl-diphenylmethyl) -imidazole

To a solution of imidazole (4.48 g) and triethylamine (6.96 g) in acetonitrile (80 ml) at room temperature was added dropwise phosphorus trichloride (3.92 g) and the mixture was stirred for 1 hour. Purified o-chlorophenyldiphenylmethanol (5.90 g) was added and the reaction mixture was refluxed for 2 hours. The solvent was evaporated and the residue was extracted with chloroform. The extract was worked up as described in Example 3. 5.72 g (33%) of 1- (o-chlorophenyldiphenylmethyl) imidazole are obtained; mp 142-143 'C.

Example 7 Preparation of 1- (o-Chloro-phenyl-diphenylmethyl) -imidazole A solution of imidazole (g) in 50 ml of chloroform was added dropwise at 10 ° C to 3.43 g of phosphorus trichloride. After 1 hour at 5-10 ° C, the precipitated imidazole hydrochloride is filtered off under vacuum and the filtrate is concentrated. To the concentrate was added 7.08 g of o-chlorophenyldiphenylmethanol and the reaction mixture was heated at 40-60 ° C for 5 minutes. Water was added and the mixture was extracted with chloroform. The extract was worked up as described in Example 3. 6.95 g (84%) of 1- (o-chlorophenyldiphenylmethyl) imidazole are obtained; mp 140-142 ° C.

Example 8

Preparation of 1-triphenylmethylimidazole

The procedure of Example 3 was followed except that triphenylmethanol was used instead of o-chlorophenyldiphenylmethanol. The resulting crystalline residue was washed with isopropyl ether. The crude 1-triphenylmethylimidazole was obtained in 98.4% yield. Recrystallization from acetonitrile gave pure product, m.p. 220-221 ° C in 83% yield.

Analysis calculated for C ₂₂ HisN ₂ : C, 85.13; H, 5.85; N, 9.03; Found: C, 85.10; H, 5.69; N, 8.97.

Example 9

Preparation of 1-triphenylmethylimidazole

The procedure of Example 7 was followed, but starting from triphenyltanol instead of o-chlorophenyldiphenylmethanol. The resulting crystalline residue is recrystallized from a mixture of acetonitrile and chloroform. The pure 1-triphenylmethylimidazole, m.p. 220-221 ° C, is obtained in 90% yield.

Example 10

Preparation of 1-triphenylmethylimidazole

The procedure of Example 2 was followed, but starting from triphenylmethanol instead of o-chlorophenyldiphenylmethanol. The resulting crystalline material is recrystallized from acetonitrile. The pure 1-triphenylmethylimidazole, m.p. 219-220 ° C, is obtained in 81% yield.

Claims (2)

A process for the preparation of N-tritylimidazole derivatives of formula (I) wherein X ₁ , X ₂ and X _{3 are} hydrogen or one of them represents halogen and the remaining two groups are hydrogen atoms from a tritylcarbinol derivative of formula (II) - wherein X ₁ , X ₂ and X ₃ are as defined above, wherein the tritylcarbinol derivative of formula (II) wherein X ₍ , X ₂ and X ₃ are as defined above) in a solvent is -5 ° C and 4 to 130 ° C. The reaction is carried out at a temperature of about 0 ° C, optionally in situ with tri- (1-imidazolyl) phosphine (III). Process for the preparation of 1 - [(2-chlorophenyl) diphenylmethyl] imidazole according to claim 1, characterized in that the tritylcarbinol derivative of the formula (II) is o-chlorophenyldiphenylmethanol we use it.