KR820002099B1 - Process for preparing substituted dibenzyl ehters - Google Patents

Abstract

Dibenzyl ethers (I; R=Ph, phenylthio), each of which showed fungicidal activity somewhat less than, and bactericidal activity superior to, those of miconazole and clotrimazole, were prepd. by the reaction of 1-(2',4',-dichlorophenyl)-2-(N-imidazolylmethyl)-ethanol and V(X=Cl, Br) at 20-100≰C for 6-36hr in solvent. Thus, 2,4-Cl2C6H3COCH2Cl was reduced by NaBH4 and the resultant alcohol was successively condensed with imidazole and 4-ClCH2C6H4SPh to give I.

Description

Process for preparing substituted dibenzyl ether

The present invention relates to a process for preparing substituted dibenzyl ethers.

More specifically, the present invention provides 2,4-dichloro-4'-phenyl-α- (N-imidazolyl-methyl) -dibenzyl ether represented by the following general formula (I) and 2,4- Dichloro-4'-phenylthio-α- (N-imidazolyl-methyl) -dibenzyl ether and a pharmacologically acceptable acid addition salt thereof are provided.

Wherein R is a phenyl or phenylthio group

As pharmacologically acceptable acid addition salts of the general formula (I), those formed from inorganic and organic acids, salts of hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, methane-sulfonic acid, succinic acid, maleic acid, fumaric acid, citric acid and tartaric acid can be used. have. These salts can be prepared by conventional methods, for example by adding a suitable acid to an equimolecular weight base and then crystallizing the obtained salt with a suitable solvent.

Compound I and its salts are beneficial because they show activity against fungi, yeast and gram positive aerobic and anaerobic bacteria. This activity is associated with low toxicity. Compounds of the present invention can be treated with two known fungal therapeutic agents, clotrimazole, ie [(imidazol-1-yl) -2- (0-chlorophenyl) -2,2-diphenylmethane] and myco Compared to miconazole.

Of particular importance is the comparison of the activity and toxicity of compound I with myconazole, ie 2,2 ', 4,4'-tetrachloro-α- (N-imidazolylmethyl) -dibenzylether. In myconazole, the benzyl groups are all substituted in the 2- and 4-positions by chlorine atoms, so in compound I the α-unsubstituted benzyl group is substituted in the 4-position by phenyl or phenylthio groups. This difference significantly reduced the toxicity, and the antifungal and antimicrobial activities were nearly identical, while the novel compounds reduced toxicity three to four times more than myconazole. The compound of the present invention can be conveniently used for topical treatment of the human body of dermatosis such as ringworm and candidosis and infectious diseases of staphylococci and streptococci. The compounds of the present invention may be mixed with pharmacologically acceptable extenders or carriers for the preparation of suitable forms of medicaments such as, for example, powders, ointments, creams, suspensions and dispersants.

The results obtained in the physiological tests are shown in Tables I, II and III.

Table I lists the acute toxicity value of Compound I (LD ₅₀ ) and that of the comparative substance. Toxicity expressed in mg / kg was evaluated by oral administration to mice by a conventional method.

Table II shows the minimum inhibitory concentration (MIC) of compound I and the comparative compound. For MIC the minimum concentration is one that can inhibit the growth of several fungi and yeasts. MIC values were measured by the usual 2-fold serial dilution method.

Table III shows the MIC values of the test product and the comparative substance measured by a conventional 2-fold serial dilution method for a certain number of Gram-positive bacteria. Experimental conditions are as follows.

[Fungus]

Medium: Sabouraud liquid pHH5.7 (5 ml per tub).

Inoculum: The agar culture was washed with a physiological solution containing 10% Tween 80 for 10 days, then filtered with gauze and again the solution was 50% T (ml) in a Coleman Jr II spectrophotometer at wavelength 650 nm. Suspended in physiological solution until 0.1 ml of sugar spore suspension). Aspergillus niger was filtered and diluted 1/10 fold in physiological solution. 0.1 ml of this dilution was used for 5 ml of inoculum.

The temperature and incubation time are 7 days at 25 ° C.

[leaven]

Medium: Saborod solution pH 5.7 (5ml per tube)

Inoculum: Yeast was inoculated in savorod solution for 24 hours [2 days for Cryptococcus neoformans]. The cells were collected by centrifugation at 6500-pm and again suspended in physiological fluid to obtain a suspension with 50% transparency (T) on Coleman Jr II at wavelength 650 nm. 0.1 ml of this suspension was used for 5 ml of inoculum. Temperature and incubation time is 48 hours at 37 ℃.

[Gram positive bacteria]

Medium: tryptic soybean juice pH 7.3 (5 ml per tube)

Inoculum: The day before the test, the microorganisms to be tested were transferred to each medium. After 18 hours of incubation at 37 ° C., 0.1 ml of the 1: 100 dilution suspension of each strain of juice was inoculated in a series of 0.009-160 mcg / ml in 5 ml of medium containing the product under test. Temperature and incubation time is 18 hours at 37 ℃.

TABLE I

Acute toxicity upon oral administration (mg / kg) of mice (LD ₅₀ )

Table II

Antifungal activity (MIC) (mcg / ml)

Table III

Antimicrobial Activity (MIC) (mcg / ml)

The present invention relates to a process for the preparation of the compounds of general formula (I) above, wherein 1- (2 ', 4'-dichlorophenyl) -2- (N-imidazolyl) -ethanol in a solvent is formulated. Concentrate with the halobenzyl compound of V.

Wherein R is as defined above and X represents chlorine or a cancel atom.

As the solvent, aromatic hydrocarbons, dimethylformamide, tetrahydrofuran, hexamethylphosphoramide and / or mixtures thereof can be used, but more complete concentration has been done when using dimethylsulfoxide. This increases the yield and requires no further purification of the product, but the above purification can be done using dimethylformamide or hexamethylphosphoramide as solvent. In fact, the silica gel column can contain a small amount of impurities by simple filtration of the base solution.

In the case of compound I, in which R represents a phenyl group, no filtration is required and the nitrate is crystallized to purify the product to a sufficient degree for pharmaceutical use. As the proton solvent, an alkali metal hydride or an amide capable of chlorideing the hydroxyl group of the ethanol derivative is usually used.

Alternatively, aliphatic alcohols having 3 to 6 carbon atoms, such as t-butanol, are used as condensation solvents, in which case alkali metal hydrides or amides are used as alkali metal alcoholates, for example potassium t-butyl. Replace at rate.

A more useful method is to add a small amount of potassium iodide as catalyst before adding the halobenzyl derivative.

1- (2 ', 4'-dichlorophenyl) -2- (N-imidazolyl) -ethanol is reduced with a keto group using sodium borohydride and condensed with imidazole to yield 1-chloroacetyl-2, It can be prepared from 4-dichlorobenzene (see Beilstein-Handbuch der Org. Chem. IVed. Vol. 7.28). Reduction and condensation may be performed in any order. The reduction reaction can be carried out in methanol, and the concentration reaction can be carried out in dimethylformamide and methanol in the presence of sodium. Halobenzene compounds of the general formula (V) are known. Preparation of 4-chloromethyl-biphenyl is described in Chem. Ber. 66B, 1471, 1933, and the preparation of 1-bromomethyl-4-phenylthiobenzene is described in US Pat. No. 3,242,193.

Examples 1-4 described hereinafter describe the present invention more specifically, while Examples A and B describe the preparation of starting materials used in Examples 1-4.

Example A

1- (2 ', 4'-dichlorophenyl) -2-chloro-ethanol

49.5 g of sodium borohydride were slowly added little by little in a suspension of 233 g of 1- (1'-hydroxy-2'-chloro-ethyl) -2,4-dichloro-benzene, which was stirred in 1 liter of methanol at room temperature. The solution thus obtained was further stirred at room temperature for 2 hours and then inclined to 1 L of ice-cold 5N hydrochloric acid. After extraction with ethyl acetate or chloroform, the extract was washed with water, IN sodium hydroxide, then with water until neutral, and finally with saturated sodium chloride solution. The extract was dried, the solvent was maintained and 220 g of oil was obtained. After standing, the oil solidified and the solid melted at 48-51 ° C.

Analysis: C ₈ H ₇ Cl ₃ O

Calculated Value: C 42.61% H 3.13% Cl 47.17%

Found: 42.75% 3.19% 47.43%

Example B

30 g of 1- (2 ', 4'-dichlorophenyl) -2- (N-imidazolyl) -ethanolsodium was added to a solution of 88.5 g of imidazole in 600 ml of methanol, and then the solvent was distilled off. The residue was dissolved in 330 ml of dimethylformamide and heated to 115-120 ° C. A solution of 225 g of 1- (2 ', 4'-dichlorophenyl) -2-chloro-ethanol dissolved in 400 ml of dimethylformamide was added dropwise to the solution thus obtained under stirring. The mixture was heated to 115-120 ° C., held at this temperature for 20 minutes and then cooled at 40 ° C., followed by the vigorous stirring of 2500 ml of ice water. The product was stirred for at least about 2 hours to precipitate, then the supernatant was decanted, 2500 ml of water was further added and left to stand, followed by filtration of the whole. The precipitate thus obtained was dried and then crystallized with toluene. 170g of the target material which melted at 134-135 degreeC was obtained.

Split Line C ₁₁ H ₁₀ Cl ₂ N ₂ O

Calculated Value: C 51.38% H 3.92% N 10.89% Cl 27.58%

Found: 51.62% 3.80% 10.73% 27.76%

Example 1

2,4-dichloro-4'-phenylthio-α- (N-imidazolyl-methyl) -dibenzyl ether (I: R = C ₆ H ₅ S)

[Method I]

5 ml of hexamethylphosphoramide was prepared by dissolving 2.57 g of 1- (2 ', 4'-dichlorophenyl) -2- (N-imidazolyl) -ethanol prepared in Example B in 10 ml of hexamethylphosphoramide. To a suspension of 0.52 g of sodium hydride (50% in oil) in water was added dropwise at 25 ° C. After the hydrogen evolution, the chloride was terminated by heating at 50 ° C. for 1 hour. After cooling to 25 ° C., 2.58 g of 1-chloromethyl-4-phenylthio-benzene was added. The temperature was raised to 50 ° C. and maintained at this temperature for 12 hours. At the end of the reaction, the mixture was decanted into 200 ml of water, the product was extracted with diethyl ether, the solvent was distilled off, and the residue was purified twice with silica gel column using ethyl acetate as eluent, and thin layer chromatography (TLC) tested various classifications. The middle fraction was distilled off with a solvent to give 2.4 g of the target base as a yellow oil having a single point on TLC.

Analysis: C ₂₄ H ₂₀ N ₂ Cl ₂ OS

Calculated Value: C 63.30% H 4.44% N 6.13% Cl 15.57% S 7.04%

Found: 63.86% 4.24% 6.41% 15.29% 6.97%

[Method II]

0.66 g of sodium hydride (50% in oil) is dissolved in 15 ml of 1- (2 ', 4'-dichlorophenyl) -2- (N-imida) in 15 ml of dimethyl sulfoxide (dried with calcium hydride) under a nitrogen atmosphere at 20 to 30 캜. To 3.86 g of zolyl) -ethanol.

The mixture was heated by stirring at 50-60 ° C. until gas evolution ceased. After cooling to 20-25 ° C., 0.5 g of potassium iodide was added, and a solution of 3.51 g of 1-chloromethyl-4-phenylthio-benzene dissolved in 4 ml of dimethyl sulfoxide was slowly added dropwise. The mixture was stirred at 20-25 ° C. until the end of addition of 1-chloromethyl-4-phenylthio-benzene. The mixture was then decanted into 150 ml of water and extracted with diethylethyl ether. After drying with anhydrous sodium sulfate in an ethereal solution, an excess of 4N nitric acid solution in diethyl ether was added, the target was precipitated as a nitrate, and the oil was left to solidify. After standing for 20 hours, the ethereal liquid was decanted off and the residue was purified by ethanol. The resulting nitrate, which was not completely pure, was dissolved in water and the excess was added to liberate the base and then extracted with ethyl acetate. The base obtained by filtration was purified by silica gel column using ethyl acetate as eluent. The combined fractions containing the desired product were evaporated to dryness. The residue was dissolved in diethyl ether, transferred back to nitrate and crystallized from ethanol. Yield: 3.1 g of white crystalline powder, melting point of 134 占 폚. Assay: C ₂₄ H ₂₀ N ₂ Cl ₂ OS. HNO ₃

Calculated Value: C 55.61% H 4.08% N 8.11% Cl 13.68 S 6.18%

Found: 55.32% 4.08% 8.16% 13.56% 6.32%

Example 2

2,4-Dichloro-4'-phenyl-α- (N-imidazolyl-methyl) -dibenzyl ether (I: R = C ₆ H ₅ )

[Method I]

A mixture of 2.02 g of potassium t-butylate in 30 ml of t-butanol was prepared at 20-25 ° C. and in a nitrogen atmosphere. 3.86 g of 1- (2 ', 4'-dichlorophenyl) -2- (N-imidazolyl) -ethanol prepared in Example B was added thereto. The solution was refluxed for 1 hour and then cooled at 20-25 ° C. 3.03 g of 4-chloromethyl-biphenyl was added and the solution was again refluxed for 5 hours. After cooling at 20-25 ° C., the whole was decanted into water and the base was extracted with ethyl acetate. The extract was washed with diethyl ether and the solvent was distilled off. The residue was dissolved in diethyl ether (80 ml) and left overnight. The insoluble matter was filtered off and the filtrate was treated with nitric acid dissolved in diethyl ether. The oil was left to solidify. The residue consisting of 2,4-dichloro-4'-phenyl-α- (N-imidazolyl-methyl) -dibenzylethernitrate was purified by ethanol or ethyl acetate. TLC was confirmed to be pure, and a product (4.3 g) having a melting point of 140 to 141 ° C was obtained.

Analysis: C ₂₄ H ₂₀ N ₂ Cl ₂ O. HNO ₃

Calculated Value: C 59.25% H 4.35% N 8.64% Cl 14.57%

Found: 59.17% 4.14% 8.61% 14.46%

[Method I (a)]

To a solution of 0.37 g of sodium metal dissolved in 20 ml of n-propanol, 4.1 g of 1- (2 ', 4'-dichlorophenyl) -2- (N-imidazolyl) -ethanol is added and the mixture is stirred with 2 It was refluxed for hours. After cooling at room temperature, 0.5 g of potassium iodide and 3.25 g of 4-chloromethane-biphenyl were added under stirring and the mixture was refluxed again. At the reaction boil this mixture was filtered off and washed with ethanol. The filtrate was evaporated to dryness and the residue was dissolved in diethyl ether. The insoluble residue was filtered off and the clear ethereal solution thus obtained was treated with a mixture of nitric acid and diethyl ether. The 2,4-dichloro-4'-phenyl-α- (N-imidazole-ylmethyl) -dibenzylethernitrate thus formed was crystallized with ethanol. A product (2.lg) having the same characteristics as that prepared by the above method and showing a single point in TLC was obtained.

[Method II]

0.66 g of sodium hydride in 20 ml of dimethyl sulfoxide (dried with calcium hydride) at 20-25 DEG C under nitrogen atmosphere in 1- (2 ', 4'-dichlorophenyl) -2- (N-imidazolyl) -ethanol To 3.86 g of solution. The mixture was heated at 50-60 ° C. until gas evolution stopped. The mixture was cooled to 20-25 ° C., and 0.5 g of potassium iodide was added thereto, and a solution of 3.03 g of 4-chloromethyl-biphenyl in 7 ml of dimethyl sulfoxide (dried with calcium hydride) was added dropwise. The whole was stirred at 20-25 ° C. for about 20 hours and then decanted in water. The product was extracted with ethyl acetate and then treated as described in method I. Yield 4.6 g

Example 3

The free base, in which the 2,4-dichloro-4'-phenylthio-α- (N-imidazolyl-methyl) -dibenzylether salt is dissolved in ethanol, is reacted with an alcohol solution of a suitable acid and then obtained with a suitable solvent. One salt was prepared by crystallization. The free base was prepared by freeing from its nitrate prepared by Example I, Method I or by Method II, treated with sodium carbonate or extracted with diethyl ether and then evaporated.

Table IV shows the crystallization solvents, elemental analysis values and melting points of some salts.

Table V shows the same data for the salts of 2,4-dichloro-4'-phenyl-α- (N-imidazolyl-methyl) -dibenzylether obtained using the methods described above.

Table IV

TABLE V

Example 4

Antifungal and antimicrobial agents are prepared which contain 0.5 to 5% by weight of the active compound according to the invention, suitably 1 to 3% by weight and a pharmacologically acceptable extender or carrier. Compositions of ointments, powders, glycolic solutions and gels are illustrated below.

Ointment

Glycolic Solution

Powder

Gel

Claims (1)

1- (2 ', 4'-diclophenyl) -2- (N-imidazolylmethyl) -ethanol is reacted for 6 to 36 hours at 20 to 100 ° C in the presence of a solvent with halobenzyl of the following general formula (V) A process for producing substituted dibenzyl ethers of the general formula (I)

Wherein R is a phenyl or phenylthio group and X is a chlorine or a cancel atom.