KR830000634B1 - How to prepare N-trityl imidazole compound - Google Patents

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Description

How to prepare N-trityl imidazole compound

The present invention relates to a novel method for preparing an N-tritylimidazole compound, and more specifically, to the present invention

General formula

[Wherein R ₁ , R ₂ and R ₃ are independently a hydrogen atom, an alkyl group or a phenyl group and X ₁ , X ₂ and X ₃ are independently an alkyl group or an electronegative component, and n ₁ , n ₂ and n ₃ is an integer of 0, 1 or 2, respectively.], and the improved method for producing the N-tritylimidazole compound.

N-trityl imidazole compounds of general formula [I] are already known to be useful as antifungal or antibacterial agents. [US Pat. Nos. 3,321,321,366 and 3,705,172]

As disclosed in the aforementioned US patent, N-tritylimidazole compounds are prepared by reacting halides or salts of tritylcarbinol derivatives with silver or sodium salts of imidazole derivatives. However, this method has some disadvantages. For example, halides and salts of trityl carbinol derivatives are unstable in water, making them difficult to prepare, silver salts of imidazole are expensive, unstable when exposed to light, and other desired yields of compounds. Is low.

N-trityl imidazole compounds are also prepared by reacting tritylcarminol derivatives with imidazole derivatives.

Unlike the known methods described above, this method does not require expensive or unstable starting materials. However, this method does not proceed smoothly under normal conditions, so in order to obtain the desired compound even at low yield, the reaction must be carried out at a very high temperature for a long time.

Thus, this method is also not satisfactory as a commodity product of N-trityl imidazole compounds.

In order to achieve a more convenient and economical method for the preparation of N-trityl imidazole compounds, extensive research has been undertaken. Now, under the mild reaction of tri (1-imidazolyl) phosphine derivatives and trityl carbinol derivatives, It has been found that it can proceed smoothly to produce N-trityl imidazole compounds in high yields. In addition, O-chloro phenyl diphenyl methanol, which is used as a starting material for the preparation of a potent antifungal compound known as Clotrimazele in the method of the present invention, is converted to benzene in the presence of aluminum chloride to benzene. It was found that the reaction mixture obtained by the Friedel-Crafts reaction can be treated with water to obtain a high yield.

Thus, the present invention provides a method for preparing an N-trityl imidazole compound of general formula [I]. This is a general formula

The trityl carbinol derivative of [wherein X ₁ , X ₂ , X ₃ , n ₁ , n ₂ and n ₃ in each formula is as defined above],

By reacting with a tri (1-imidazolyl) phosphine derivative of [wherein R ₁ , R ₂ R ₃ are each as defined above].

Preferably, the present invention treats the reaction mixture obtained by reacting O-chlorobenzotrichloride with benzene in the presence of aluminum chloride with water to give O-chlorophenyldiphenylmethanol. It is to provide a method for producing 1-[(2-chlorophenyl) diphenylmethyl] -imidazole formed by reacting with (1-imidazolyl) phosphine.

Alkyl groups for R ₁ , R ₂ R ₃ X ₁ , X _2, and X ₃ which are suitable in the foregoing and in the following description are preferably straight chains having 1 to 12 carbon atoms, suitable being 4 carbon atoms in 1 It is a branched alkyl group.

Examples of suitable alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl and the like.

Examples of the electronegative component include halogen (eg, fluorine, chlorine, cancellation, oxo), nitro, trifluoromethyl, cyano, alkylthio and alkoxy. As alkylthio and alkoxy, those having 1 to 4 turno atoms are suitable.

In the method of the present invention, the N-trityl imidazole compound of the general formula [I] is usually a tri (1-imidazolyl) phosphine derivative of the general formula [III] as the trityl carbinol derivative of the general formula [II]. As suitable in the temperature range of about -5 to 130 ℃ is prepared by reacting at about 0 to 100 ℃ in a suitable solvent.

몰 이상의 량으로 사용하는데 양호한 결과는 1몰의 트리틸 카르비놀 유도체〔Ⅱ〕에 대하여

내지 3몰의 트리(1-이미다졸릴)포스핀 유도체〔Ⅲ〕를 사용하는 경우에 얻어진다.In carrying out this reaction, tri (1-imidazolyl) -phosphine derivative [III] is generally used with respect to 1 mole of trityl carbinol derivative [II].

Good results for use in an amount greater than or equal to 1 mole are given for 1 mole of trityl carbinol derivatives [II].

To 3 moles of tri (1-imidazolyl) phosphine derivative [III].

Solvents used in the process include aromatic hydrocarbons such as benzene and toluene, halogenated aliphatic hydrocarbons such as chloroform or dichloromethane, tetrahydrofuran, methyl isobutyl ketone, dimethylformamide, pyridine, acetonitrile and mixtures thereof. Can be illustrated.

Trityl carbinol derivatives [II] and tri- (1-imidazolyl) phosphine derivatives [III] used as starting materials are already known and can be manufactured by a well-known method. [J. Org. Chem., 7, 392 (1942); J. Am. Chem. Soc., 33, 531 (1911); Anegw. Chem., 73, 143 (1961)]

Tri (1-imidazolyl) phosphine derivative [III] is also a general formula

Prepared by reacting an imidazole derivative of [wherein R1, R2 and R3 are each as defined above] with phosphorus trichloride in the presence of an acid-binding agent in a suitable solvent.

Tri (1-imidazolyl) phosphine derivative [III] is sensitive to moisture. Therefore, it is convenient to react with trityl carbinol derivative [II] in solution without separating it.

The following examples are intended to more precisely specify the invention, which are not intended to limit the invention.

Example 1

(A) Preparation of O-chlorophenyl diphenyl methanol:-

Benzene (380 ml) was poured into the flask, and aluminum chloride (88 g) was suspended in the flask.

A solution of O-chloro benzotrichloride (138 g, 0.6 mol) in benzene (145 ml) was added dropwise for 2 hours while maintaining the temperature at 60 ° C. After completion of the stock price, the mixture was refluxed for 2 hours.

The reaction mixture was poured into water (600 ml) and washed with its flask benzene (240 ml) and water (120 ml).

This compound mixture was refluxed for 4 hours. The organic layer was separated, washed with water (400 ml), treated with charcoal (6 g) and filtered. The benzene filtrate was evaporated to afford 172.6 g of O-chloro phenyl diphenyl methanol in the amount of crystals. Yield 97.7%, Melting Point 88.5-91.5 ° C

(B) Purification of O-chlorophenyl diphenyl metalol:-

80 g of O-chloro phenyl diphenyl methanol (melting point 88.5 to 91.5 ° C.) obtained in (A) was recrystallized in isopropanol to yield 71 g of a purified compound having a melting point of 92 to 94 ° C.

Elemental Analysis: Theoretical for C ₁₉ H ₁₅ OCl: C, 77.41%; H, 5.13%; CI, 12.03%, found C, 77.58; H, 5.0 1%; Cl, 12.30.

Example 2

Preparation of 1- (O-chlorophenyl diphenyl methyl) -imidazole:

To a solution of tri (1-imidazolyl) phosphine (0.99 g, 4.3 mmol) in chloroform (30 ml) was added O-chloro phenyl diphenyl methanol (2.50 g, 8.5 mmol) obtained in Example 1 (B). It was added dropwise at 0 to 10 ° C. Water was added and the mixture was extracted with chloroform. The extract was washed sequentially with 5% aqueous sodium hydroxide solution and water, dried over magnesium sulfate and evaporated to produce a residue. Recrystallization from acetonitrile gave 2.2 g of 1- (O-chloro phenyl diphenyl methyl) imidazole.

Yield, 75%, Melting Point, 142-143 ° C

Elemental Analysis: Theoretical for C ₂₂ H ₁₇ N ₂ Cl: C, 76.63%; H, 4.97%; N, 8.12%. Found C, 76.53; H 4.65%; N, 8.41%.

Example 3

Preparation of 1- (O-chlorophenyl diphenyl methyl) -imidazole:

To a solution containing 122.4 g (1.8 mole) imidazole and 181.8 g (1.8 mole) triethylamine in 1200 ml of chloroform, 88.2 g (0.6 mole) of phosphorus trichloride was added dropwise by stirring at 0 to 10 ° C. The mixture was stirred for 1 hour. To the resulting solution, 172 g of O-chloro phenyl diphenylmethanol obtained in Example 1 (A) was added, and the mixture was refluxed for 1 hour.

After cooling, water was added and the mixture was exported to chloroform. The extract was washed successively with 10% aqueous potassium carbonate solution and water, dried over magnesium sulfate, treated with charcoal (18 g) and filtered.

Evaporation of this filtrate yielded 240 g of oily residue.

This residue was crystallized in acetonitrile (180 mmol) to yield 159 g of 1- (O-chloro phenyl diphenylmethyl) imidazole. Yield 71.1%, Melting Point, 142-143 DEG C,

This crude compound was recrystallized in acetonitrile (330 ml) to yield 144.2 g of 1- (O-chloro phenyl diphenyl methyl) -imidazole. Yield 69%, Melting Point, 143-144 占 폚,

Example 4

Preparation of 1- (O-chlorophenyl diphenyl methyl) -imidazole:

To a solution containing 2.24 g (33 mmol) of imidazole and 3.03 g (33 mmol) of triethylamine in 40 ml of chloroform, 1.51 g (11 mmol) of phosphorus trichloride was added dropwise at 5 to 15 ° C, The mixture was stirred for 1 hour. To this solution was added 2.95 g (0.01 mol) of O-chloro phenyl diphenylmethanol obtained in Example 1 (B), and the mixture was refluxed for 2 hours. This reaction mixture was treated in the same manner as in Example 3 to yield 3.10 g of 1- (O-chloro phenyl diphenyl methyl) imidazole.

90% yield, melting point, 140-142 degreeC

Example 5

Preparation of 1- (O-chlorophenyl diphenylmethyl) -imidazole:

To a solution containing 2.24 g (33 mmol) of imidazole and 3.03 g (33 mmol) of triethylamine in 40 ml of toluene, 1.51 g (11 mmol) of phosphorus trichloride was added dropwise at 5 to 15 ° C, The mixture was stirred for 1 hour. To this reaction mixture was added 2.95 g (0.01 mol) of O-chloro phenyl diphenylmethanol obtained in Example 1 (B), and the mixture was refluxed for 2 hours. After cooling, water (40-50 ml) was added thereto. The organic layer was separated, washed successively with 5% aqueous potassium carbonate solution and water, dried over magnesium sulfate and evaporated.

This residue was determined in acetonitrile to yield 2.76 g of 1- (O-chloro phenyl diphenylmethyl) -imidazole. Yield 80%, Melting Point, 142-143 ° C

Example 6

Preparation of 1- (O-chlorophenyl diphenyl methyl) imidazole:

3.92 g of phosphorus trichloride was added dropwise at room temperature to a solution containing 4.48 g of imidazole and 6.96 g of triethylamine in 80 ml of acetonitrile, and the mixture was stirred for 1 hour.

O-chloro phenyl diphenyl methanol (5.90 g) obtained in Example 1 (B) was added and the mixture was refluxed for 2 hours.

The solvent was evaporated and the residue was refluxed for 2 hours.

The solvent was evaporated and the residue was extracted with chloroform. This extract was treated in the same manner as described in Example 3 to yield 5.72 g of 1- (O-chloro phenyl diphenylmethyl) imidazole.

83% yield, melting | fusing point, 142-143 degreeC

Example 7

Preparation of 1- (O-chlorophenyldiphenylmethyl) -imidazole:

To a solution containing 10 g of imidazole in 50 ml of chloroform, 3.43 g of phosphorus trichloride was added dropwise at 10 ° C. The mixture was kept at 5-10 DEG C for 1 hour, filtered through suction by precipitation of imidazole hydrogen chloride, and the filtrate was concentrated. O-chloro phenyl diphenyl methanol (7.08 g) was added and the mixture was heated to 40-60 ° C. for 5 minutes. Water was added and the mixture was extracted with chloroform. This extract was treated in the same manner as in Example 3 to yield 6.95 g of 1- (O-chloro phenyl diphenyl methyl) -imidazole.

Yield 84%, Melting Point, 140-142 ° C

Example 8

Preparation of 1-triphenylmethyl imidazole:

The reaction was carried out in the same manner as in Example 3 using triphenyl methanol instead of O-chloro phenyl diphenyl methanol. The obtained crystal residue was washed with isopropyl ether to give crude 1-triphenyl methyl imidazole. Recrystallization in acetonitrile yield 98.4% yielded purified 1-triphenyl methylimidazole in 83% yield. Melting Point, 220 ~ 221 ℃

Elemental analysis: Theoretical value for G ₂₂ H ₁₈ N ₂ : G, 85.13%, H, 5.85%, N, 9.03%, Found: C, 85.10%, H, 5.69%, N, 8.97%.

Example 9

Preparation of 1-triphenyl methyl imidazole:

The reaction was carried out in the same manner as in Example 7 using triphenyl methanol instead of O-chloro phenyl diphenyl methanol. The obtained crystal residue was recrystallized in acetonitrile-chloroform to produce purified 1-triphenyl imidazole in 90% yield. Melting Point, 220 ~ 221 ℃

Example 10

Preparation of 1-triphenylmethyl imidazole:

The reaction was carried out in the same manner as in Example 2 using triphenyl methanol instead of O-chloro phenyl diphenyl methanol. The obtained crystals were recrystallized in acetonitrile to produce purified 1-triphenylmethyl imidazole in a yield of 81%. Melting Point, 219-220 ℃

Claims (1)

The trityl carbinol derivative of the following general formula [II] was reacted with the tri (1-imidazolyl) phosphine derivative of the following general formula [III] at a temperature of -5 to 130 ° C. to give the following general formula [I] Of preparing an N-trityl imidazole compound.

In which R ₁ , R ₂ and R ₃ are independently hydrogen, alkyl or phenyl; ₁ , X ₂ and X ₃ are independently an alkyl group or an electro-negative component, and n ₁ , n ₂ and n ₃ are integers of 0, 1 or 2, respectively.