MXPA99005884A - Process for producing imidazole derivatives - Google Patents

Abstract

A process for producing compounds of general formula (III), wherein R1 and R3 each represents a hydrogen atom or an organic residue;R2 represents an organic residue;and R4 represents a substituted or unsubstituted aryl group, by reacting a compound of general formula (I), wherein R1, R2 and R3 are each as defined above with a compound of general formula (II) R4-S-Hal, wherein R4 is as defined above;and Hal represents a halogen atom, in the presence of a base.

Description

PROCESS TO PRODUCE IMIPAZOLE DERIVATIVES FIELD OF THE TECHNIQUE The present invention relates to a process for producing imidazole derivatives.

ANTECEDENTS OF THE TECHNIQUE Different imidazole derivatives have been sought for application to medicines, and the present inventors found that the imidazole derivatives having an arylthio group at position 5 were efficient as antiviral agents or anti-HIV agents.

It is known that a process for producing imidazole derivatives having a group, substituted thio, the halogenated imidazole derivatives react with mercaptans / NaH / DMF after the formation of a ring of Ref .: 30527 amidazole (HETEROCYCLES, Vol. 33, No. 1, 21-26, (1992)). It is also known that the imidazole derivatives react with bisulfide in the presence of a base after the halogenation of -CH of the amidazole ring (J. Chem. Perkin Trans. I 1139-1145 (1989) and WO 96/10019). These methods, however, are inappropriate for the reaction on an industrial scale because they require halogenation of the -CH of the imidazole ring and a strong base such as NaH or the like. As mentioned above, a process for producing imidazole derivatives having a substituted thio group, which is suitable for convenient, economical, large-scale production, has not been known so far.

BRIEF DESCRIPTION OF THE INVENTION The present invention has intensively studied the development of convenient, economical, large-scale production of imidazole derivatives with substituted thio groups such as 5-arylthio imidazole derivatives, and which are successful in the reaction of imidazole derivatives of the following formula (I) with thiohalide of the formula (II) in the presence of a base to give imidazole derivatives having a substituted thio group of the formula (III). Thus, the present invention has been realized.

Accordingly, the present invention provides a process for producing a compound of the formula (III): wherein R1 and R3 are independently hydrogen or an organic group; R2 is an organic group; and R 4 is an optionally substituted aryl, which comprises reacting a compound of the formula (I): Where R \ R 'and R are as defined above, with a compound of the formula (II): R -S-Hal II Where R is as defined above and Hal is halogen, in the presence of a base.

THE BEST MODALITY TO CARRY OUT THE INVENTION A preferred embodiment of the present invention includes the process wherein the organic groups in the formula (I) are optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, a substituted thioaryl or substituted pyridione, an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl, an optionally substituted aralkyl, an optionally substituted acyl, an optionally substituted carbamoyl, an optionally substituted alkoxycarbonyl, -CH = N0H, -CH = NNH2, or -AX where A is -CH2OCH2- or -CH20- and X is an optionally substituted aryl , or -COR5 wherein R5 is an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted aryl, or an optionally substituted amino.

The most preferred embodiment of the present invention is (1) the process wherein R1 is hydrogen or an optionally substituted heteroalkyl; R2 is -A-X where A is -CH20CH2- or -CH20- and X is an optionally substituted aryl, or -COR5 where R5 is an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted aryl, or an optionally substituted amino; and R3 is an optionally substituted alkyl. In particular, the process for producing the compound wherein R 1 is optionally substituted pyridylmethyl is preferred (eg, pyridin-4-ylmethyl). Especially, the process for the compound wherein R2 is preferred is benzyloxymethyl, acetyloxymethyl, benzoyloxymethyl, methylcarbonyloxymethyl, and carbamoyloxymethyl.

A preferred compound of the formula (II) is (2) 3,5-dichlorobenzenesulfenyl chloride.

A preferred base is (3) triethylamine or N-ethylmorforin.

The terms used in the present specification are defined below.

The term "organic group" refers to an optionally substituted alkyl, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, an optionally substituted arylthio, an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl, an optionally substituted aralkyl, an optionally substituted acyl, an optionally substituted carbamoyl, an optionally substituted alkoxycarbonyl, -CH = N0H, -CH = NNH2, or -AX where A is -CH2OCH2- or -CH20- and X is an optionally substituted aryl, or -COR5 where R5 is an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted aryl, or an optionally substituted amino; and similar. The term "alkyl" means a C 1 -C 20 straight or branched chain alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i- prntyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. A C1-C6 low molecular weight alkyl is preferred. The "alkyl" portion of the term "alkoxy" means an alkyl as defined above, for example, methoxy, ethoxy, propoxy, t-butoxy, and the like. The term "alkenyl" means a straight or branched C2-C20 alkenyl, for example, vinyl, allyl, propenyl, butenyl, pentenyl, hexienyl, heptenyl, and the like. A C2-C7 low molecular weight alkenyl is preferred. The term "aryl" means phenyl or naphthyl. Examples of an optionally substituted aryl include, for example, 3,5-dichlorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3,5-dimethoxyphenyl, 2,4,6-trimethylphenyl, 3 , 5-di-t-butylphenyl, 4-methoxyphenyl, 4-benzylphenyl, 4-hydroxyphenyl, 3,5-dinitrophenyl, 3-nitrophenyl, 3,5-diaminophenyl, 3-aminophenyl, and the like.

The term "heteroaryl" means a heterocyclic group of 5-7 members containing at least one hetero atom (N, 0 or S), for example pyridyl (for example 4-pyridyl), pyrimidinyl (for example, 2-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl), thienyl (e.g., 2-thienyl), quinolyl (e.g., 3-quinolyl), imidazolyl (e.g., 2-imidazonyl), oxazolyl (for example, 2-oxazolyl), thiazolyl (for example, 5-thiazolyl), and the like. Pyridyl is preferred.

The term "heteroarylalkyl" means the alkyl defined above substituted with the heteroaryl defined above, for example, pyridylmethyl (e.g., 4-pyridylmethyl), pyridylethyl (e.g., 1- or 2- (2-pyridyl) ethyl), pyridylpropyl ( for example, 3- (2-pyridyl) propyl), thienylmethyl (e.g., 2-thienylmethyl), quinilylmethyl (e.g., 3-quinolylmethyl), imidazolylmethyl (e.g., 2-imidazolylmethyl), and the like.

The term "aralkyl" means the alkyl defined above substituted with the aryl defined above, for example, benzyl, phenethyl (e.g., 1-phenethyl), naphthylmethyl, naphthylethyl (e.g., 2-naphthylethyl), and the like.

The term "acyl" means an aliphatic or aromatic acyl, for example, acetyl, propionyl, pivaloyl, benzoyl, and the like.

The "optionally substituted carbamoyl" may optionally be mono- or di-substituted with a substituent as described below, for example, N-methylcarbamoyl, N, N-dimethylcarbamoyl and the like.

The term "alkoxocarbonyl" refers to, for example, methoxycarbonyl, ethoxycarbonyl, and the like.

The term "halogen" means fluorine, chlorine, bromine, and iodine. Chlorine or bromine is preferred.

The "optionally substituted amino" may optionally be mono- or di-substituted with a substituent as described below, for example, methylamino, dimethylamino and the like.

When each of the groups described above is substituted, the substituent refers to for example, an alkyl (for example, methyl t ethyl), a halogen (fluorine, chlorine, bromine and iodine), an acyl (e.g. acetyl and benzoyl), an alkenyl (e.g., allyl), a cycloalkyl (e.g., cyclopropyl), an aralkyl (e.g., benzyl), an optionally substituted amino (e.g., methylamino and dimethylamino), hydroxy, oxo, a alkoxy (for example, methoxy and ethoxy), cyano, carboxy, an alkoxycarbolyl (e.g., methoxycarbolyl), nitro, an acyloxy (e.g., acetyloxy), an optionally substituted carbamoyl (e.g., N-ethylcarbamoyl), an optionally substituted ioloxy carba (e.g., N-ethylcarbamoyloxy), and the like. One or more substituent (s) can be in any position (s). When the substituent interferes with the reaction or a protecting group can be introduced before the reaction, and then removed at any suitable step after the reaction.

The compound of the formula (I), the starting materials of the present invention, include known ones and can be produced according to the method described in International Patent Publication WO 96-10019 and Unexamined Publication of Japanese Patent 116242 / 1994. The compound of the formula I used in the present invention is, for example, 2-benzyloxymethyl-4-isopropyl-imidazole, 2-benzyloxymethyl-1-4-isopropyl-. { 1- (4-pyridylmethyl)} imidazole, 2-acetyloxymethyl-4-isopropyl-. { 1- (4-pyridylmethyl)} imidazole, 2-benzoyloxymethyl-4-isopropyl-. { 1- (-pyridylmethyl)} -imidazole, 2-methoxycarbonyloxymethyl-4-isopropyl-. { 1- (4-pyridylmethyl) Jimidazole, 2-carbamoyloxymethyl-4-isopropyl-. { 1- (4-pyridylmethyl) Jimidazole, and the like.

The compound (II) is commercially available or produced by reaction of the corresponding bisulfide (R4-S) 2 where R4 is an optionally substituted aryl, which is produced according to the known methods, with chlorine gas. The bisulfide is, for example, bis (3,5-dichlorophenyl) bisulfide, bis (4-chlorophenyl) bisulfide, bis (2-chlorophenyl) bisulfide, bis (4-nitrophenyl) bisulfide, bis (2-bisulfide) bisulfide. -nitrophenyl), bis (2,4-dinitrophenyl) bisulfide, bis (4-methoxyphenyl) bisulfide, bis (4-methylphenyl) bisulfide, bis (2,4,6-trimethylphenyl) bisulphide, and biphenyl bisulphide , and similar. The amount of chlorine gas used in the preparation of compound (II) is 1-3 mol equivalents to the bisulfide (R4-S) 2. The reaction can be carried out by introducing chlorine gas at -30-60 ° C into an organic solvent (for example, tetrachloromethane, chloroform, dichloromethane, toluene) where an adequate amount of bisulfide is dissolved.

Compound (II) is, for example, 3,5-dichlorobenzenesulfenyl chloride, 2-chlorobenzenesulfenyl chloride, 4-nitrobenzenesulfenyl chloride, 2-nitrobenzenesulfenyl chloride, 2,4-dinitrobenzenesulfenyl chloride, 4-methoxybenzenesulfenyl chloride, chloride. of 4-methylbenzenesulfenyl, 2,4,6-trimethylbenzenesulfenyl chloride, and the like A base used for the reaction of the compound (I) with the compound (II) is, for example, triethylamine, N-methylmorpholine, pyridine, N, N-dimethylaniline, N, N-diisopropyl-N-ethylamine, butyllithium, diazabicycloundecene, and the like. A solvent is for example, acetonitrile, toluene, dichloromethane, chloroform, dimethylformamide, nitromethane, benzene, tetrahydrofuran, and the like.

In the reaction of the present reaction, the amount of a base is 0.1-3 mol equivalents, preferably 1-2 mol equivalents for the compound (I) and the amount of the compound (II) is 1-3 mol equivalents, preferably 1 mol. -2 mol equivalents for the compound (I) The reaction temperature can be -30-60 ° C, preferably 0-10 ° C. The reaction time can be 0.5-24 hours, preferably 0.5-3 hours. (I) can be added generally to the compound (II) with stirring and vise versa A base is the mixture with the compound (I) at the beginning or added at the end.

The following examples are provided as another illustration of the present invention and were not constructed as limiting the scope thereof.

The meanings of the following abbreviations in the examples are shown below.

Me Metyl Ph Phenyl Bn Benzyl TEA Triethylamine DMF N, -dimethylformamide Reference Example 1 Chloride of 3,5-dichlorobenzenesulfenyl r? \ Bis (3,5-dichlorophenyl) bisulfide 15.0 g (42.1 mmol) was dissolved in tetrachloromethane (60 mL). The solution was added dropwise to a solution of chlorine gas 9.0 g (126.9 mmol) in tetrachloromethane (50 ml) at -10 ° C. The mixture was kept for 20 min. at the same temperature, where dry nitrogen gas was bubbled to remove the excess chlorine. The resulting mixture was concentrated under reduced pressure to yield objective (2) 18.6 g (quantitative) as a red oil. 1 H-NMR (CDCL3-TMS) d ppm: 7.32 (t, J = 1.8 Hz, HH), 7.43 (d, J = 1.8 Hz, 2H) Reference Example 3, 5-Dichlorobenzenesulfenyl Chloride (2) Bis (3,5-dichlorophenyl) bisulfide was dissolved 30 g (84.2 mmol) in toluene (90 ml). Chlorine gas 11.9 g (167.8 mmol) was introduced into the solution under ice cooling for 1 hour. Dry nitrogen gas was bubbled into the mixture at the same temperature to remove the excess chlorine to produce the toluene solution of the objective (2). Producing 99.7%.

Example 1 2-Benzyloxymethyl-5- (3,5-dichlorophenylthio) -4-isopropyl-1H-imidazole (3) 2-Benzyloxymethyl-4-isopro-yl-lH-imidazole (1) 50 mg (2.4 mmol) was dissolved, described in Example 1 in WO 96/10019, in a mixture of triethylamine 360 mg (3.6 mmol) and acetonitrile 4mi. 3,5-Dichlorobenzenesulfenyl chloride (2) 930 mg (4.4 mmol) was added to the solution at room temperature. The mixture was stirred for 30 minutes at room temperature and 15 ml and 15 ml toluene were added to this water. The toluene layer was separated, washed with water 10 ml twice, and concentrated under reduced pressure. The yellow oil obtained was crystallized with 10 ml diisopropyl ether, filtered, and dried to obtain the objective (3) 800 mg as a pale yellow crystal. Producing 82% 1 H-NMR (CDCL3-TMS) d ppm: 1.22 (d, J = 7.2 Hz, 6H), 3.64 (sept, ÍH), 4.62 (s, 2H), 4.67 (s, 2H), 6.92 (bs, 2H), 7.07 (bs, ÍH), 7.36 (s, 5H), 9.20 (b, ÍH).

Example 2 2-Benzyloxymethyl-5- (3,5-dichlorophenylthio) -4-isopropyl-1- (pyridin-4-yl) eti-1-H-imidazole (5) It was dissolved in toluene (50 ml) of 2-benzyloxymethyl-4-isopropyl-1- (pyridin-4-yl) -1H-imidazole (4) 10 g (31.1 mmol). The solution in the form of drops was added to a solution of toluene 24.7 g with 3,5-dichlorobenzenesulfenyl chloride (2) 8.0 g (37.5 mmol) under ice cooling for 30 minutes. Triethylamine 3.5 g (34.6 mmol) was added dropwise to the mixture under ice cooling for 1 hour, and the mixture was stirred at the same temperature for 1.5 hours. 25 ml of water were added to the mixture and the toluene layer was separated. The toluene layer was washed with 25 ml of water and each aqueous layer was extracted with 10 ml toluene. The toluene layer was collected, concentrated under reduced pressure, crystallized with 50 ml diisopropyl ether, filtered and dried for objective (5) 12.6 g as a pale yellow crystal. Production 83.3%.

XH-NMR (CDCL3) d ppm: 1.30 (d, J = 7.2 Hz, 6H), 3.08-3.22 (m, HI), 4.52 (s, 2H), 4.62 (s, 2H), 5.16 (s, 2H) , 6.65 (d, J = 1.8 Hz, 8H), 6.79 (d, J = 6.0 Hz, 2H), 7.03 (t, J = 1.8 Hz, ÍH), 7.18-7.36 fm, 5H), 8.38 (d, J = 6.0 Hz, 2H).

Reference Example 3 2-Acetyloxymethyl-4-isopropyl-1- (pyridin-4'-yl) methyl-1H-imidazole (7a) Compound (4) 20.0 g (62.2 mmol) in 100 ml of 35% aqueous hydrochloric acid was suspended. The solution was heated to 85 ° C and stirred for one hour. The reaction mixture was cooled to room temperature, and 100 ml of water and 44 ml of toluene were added. The aqueous layer was separated, neutralized with 30% aqueous sodium hydroxide, and stirred after the addition of 30 ml of ethyl acetate. The suspension obtained was filtered, washed with cold water and dried to yield 2-hydro-imet-il-4-isopropyl-1- (pidirin-4-yl) -1H-imidazole (6) 11.7 g. Production 81.4%.

XH-NMR (CDCL3) d ppm: 1.16 (d, J = 7.0 Hz, 6H), 2.68-2.89 (m, ÍH), 4.59 (s, 2H), 5.23 (s, 2H), 6.51 (s, ÍH), 7.03 (d, J 6.0 Hz, 2H) 8.55 (d, J = 6.0 Hz, 2H).

Acetyl chloride 1.32 g (17 mmol) was added in the form of drops to a solution of the hydroxy compound obtained above (6) 3.49 g (15 mmol), dichloromethane 35 ml and triethylamine 1.83 g (18 mmol) under ice-cooling and The mixture was stirred for one hour under ice cooling. Water was added thereto, and the dichloromethane layer was separated, concentrated and purified by silica gel column chromatography (elution with ethyl acetate: methanol = 10: 1) to yield the objective (7a) 3.34 g. . Performance 81.1%.

XH-NMR (CDCL3) 6 ppm: 1.26 (d, J = 7.0 Hz, 6H), 1.85 (s, 3H), 2.88-3.05 (m, 1H), 5.11 (s, 2H), 5.15 (s, 2H), 6.64 (s, ÍH), 6.95 (d, J = 6.0 Hz, 2H), 8.59 (d, J = 6.0 Hz, 2H).

According to the same method described above, the hydroxy compound obtained above (6) was reacted 1.16 g (5 mmol), dichloromethane 12 ml triethylamine 0.86 g (8.5 mmol) and benzoyl chloride 1.16 g (8.3 mmol) to produce the objective (7b) 1.65 g. Yield 93.2%. (elution: ethyl acetate).

XH-NMR (CDCL3) d ppm: 1.34 (d, J = 7.0 Hz, 6H), 2.90-3.10 (, ÍH), 5.29 (s, 2H), 5.45 (s, 2H), 6.74 (s, ÍH), 6.99 (d, J = 6.0 Hz, 2H), 7.30-7.90 (, 5H), 8.55 (d, J = 6.0 Hz, 2H).

According to the same method described, the hydroxy compound obtained above (6) 1.16 g (5 mmol), dichloromethane 12 ml triethylamine 0.76 g (7.5 mmol) and methyl chloroformate 0.70 g (7.4 mmol) was reacted to produce the objective (7c) 1.65 g, the methoxycarbonyloxy derivative, 0.40 g. Yield 27.6%.

XH-NMR (CDCL3) d ppm: 1.25 (d, J = 7.0 Hz, 6H), 2.80-3.00 (, ÍH), 3.70 (s, 3H), 5.17 (s, 2H), 5.18 (s, 2H), 6.64 (s, ÍH), 6.97 (d, J = 6.0 Hz, 2H), 8.59 (d, J = 6.0 Hz, 2H).

Example 3 2-Acetyloxymethyl-5- (3, 5-dichlorophenytio) -4-isopropyl-1- (pyridin-4-yl) ethyl-lH-imidazole (8) A solution of compound (7a) 0.87 g (3.2 mmol) in acetonitrile was added dropwise to a solution of 1.88 g of compound (2) 0.97 g (4.5 mmol) in toluene under ice cooling for 30 minutes. The solution was added in the form of drops triethylamine 0.46 g (4.5 mmol) and acetonitrile 0.5 ml to it for 15 minutes and the mixture was stirred under ice cooling for 2 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The extract was washed with water, concentrated under reduced pressure, and purified by column chromatography on silica gel (elution with ethyl acetate) to yield the objective (8) 1.17 g as a crystal. Performance 82%. p.f. 133-135 ° C.

XH-NMR (CDCL3-TMS) d ppm: 1.31 (d, J = 6.0 Hz, 6H), 1.85 (s, 3H), 3.18-3.30 (m, 1H), 5.18 (s, 2H), 5.19 (s, 2H), 6.69 (d, J = 2.0 Hz, 2H), 6.78 (d, J = 6.0 Hz, 2H), 7.05 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 6 Hz, 2H) .

Reference Example 4 2-hydroxymethyl-5- (3,5-dichlorophenylthio) -4-isopropyl-1- (pyridin-4-yl) met il-H-imidazole (9 Aqueous sodium hydroxide 1N 0.82 ml was added to a 3.5 ml suspension of compound (8) 0.35 g (0.77 mmol) in ethanol obtained in example 3. The reaction mixture was stirred for 30 minutes, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure to yield the objective (8) 0.31 g. Performance 96.9%.

Reference example 5 2-carbamoyloxymethyl-4-isopropyl-1- (pyridin-4-yl) methyl-1H-imidazole (10) The hydroxy compound (6) 15.0 g (64.9 mmol) in 150 ml acetonitrile was suspended. Anhydrous hydrochloric acid 5.2 g (142.5 mmol) in ethyl acetate 42 ml was added to the solution in the form of drops at room temperature. The mixture was cooled to 0 ° C under a nitrogen atmosphere, and chlorosulfonyl isocyanate 22.0 g (155.4 mmol) was added thereto under cooling for 45 minutes. The reaction mixture was stirred at the same temperature for 1 hour and 13.5 ml and 35.5% aqueous hydrochloric acid 13.5 ml were added thereto. The mixture was stirred at 45 ° C for 1 hour, it was cooled to room temperature and neutralized with 20% aqueous sodium carbonate. The mixture was held stationary and separated. The organic layer was washed with water and the aqueous layer was extracted with ethyl acetate. The organic layer was collected, concentrated and dried. 80 ml of isopropyl ether were added to the residue, and the solution was stirred for 1 hour at room temperature. The obtained suspension was filtered, washed with isopropyl ether, and dried to yield the objective (10) 14.8 g (83.2% yield).

XH-NMR (CDCL3-TMS) d ppm: 1.25 (d, J = 7.0 Hz, 6H), 2.80-3.00 (m, ÍH), 4.95 (bs, 2H), 5.10 (s, 2H), 5.20 (s, 2H), 6.63 (s, ÍH), 6.97 (d, J - 5.2 Hz, 2H), 8.57 (d, J = 5.0 Hz, 2H). , 7.05 (d, J = 2.0 Hz, ÍH), 8.45 (d, J = 6 Hz, 2H).

Example 4 2-carbamoyloxy-t-lime-5- (3,5-dichlorophenylthio) -4-isopropyl-1- (pyridin-4-yl) -methyl-lH-imidazole (11) 11 Compound (10) 250 mg (0.91 mmol) was dissolved in 4 ml of N, N-dimethylformamide. The solution was cooled to -30 ° C under a nitrogen atmosphere. Four times 150 mg of a solution of compound (2) 77 mg (0.36 mmol) in toluene and 150 mg of triethylamine 3 (-mg (0.36 mg) in toluene were added to the solution 4 times and 150 mg of the solution of the solution was added to the solution. Compound (2) 77 mg (0.36 mmol) in toluene The reaction mixture was stirred at -30 ° C for 30 minutes and ethyl acetate and sodium bicarbonate were added thereto.The objective (11) was extracted with ethyl acetate. ethyl dilute aqueous hydrochloric acid was added thereto, and the objective was again dissolved in the aqueous layer.The aqueous solution was neutralized with aqueous sodium bicarbonate and extracted with ethyl acetate.The extract was dried over anhydrous sodium sulfate and it was concentrated under reduced pressure to prepare the oily residue The oily residue was dissolved in 0.9 ml of methanol and 0.7 ml of water was added for 1-2 minutes at room temperature to prepare the precipitate The suspension was stirred for 30 minutes at room temperature ambi Then, stirring further for 30 minutes under cooling with ice, filtered, washed with 50% aqueous methanol and dried to yield the objective (11) 250 mg as a white crystal. Performance 61%. p. F. 88 ° C (dec) XH-NMR (CDCL3-TMS) d ppm: 1.32 (d, J = 6.9 Hz, 6H), 3.17 (sept, ÍH), 4.53 (b, 2H), 5.21 (s, 2H), 5.27 (s, 2H), 6.69 (d, J = 1.6 Hz, 2H), 6. 82 (d, J = 5.2 Hz, 2H), 7.06 (t, J = 1.6 Hz, 1H), 8.46 (b, 2H).

Element Analysis (C2oH2oCl2N 02S • 0.5H2O) (%) Cale: C, 52.16: H, 4.61: N, 12.17: S, 6.96: Cl, 15.42 (%) found: C, 52.45: H, 4.72: N, 11.73 : S, 7.08: Cl, 14.81 Salt of the compound (11) 2HC1: p. F. 214-222 ° C (dec) Reference example 6 (I) 2,2-dichloro-3-methylbutylaldehyde (13) Chlorine 316 g (4.46 mol) was introduced into the mixture of isovalelaldehyde (12) 192 g (2.23 mol) and N, N-dimethylformamide 230 mg below 60 ° C. The mixture was cooled, 384 ml was mixed with water, and separated. The organic layer was washed with 350 g aqueous sodium bicarbonate, each aqueous layer was extracted with 115 ml of toluene. The organic layer was collected to produce the toluene solution 440 g of the objective (13). (75% yield). 1H-NMR (CDCL3-TMS) d ppm: 1.15 (d, J = 6.6 Hz, 6H), 2.56 (sept, J = 6.6 Hz, ÍH), 9.24 (s, ÍH).

(II) 1,4-dibenzyloxy-2-butene (15) 14 15 Tetra-n-butylammonium bromide 3.3 g (10 mmol) was added to 48% aqueous sodium hydroxide, and the mixture was heated to 60 ° C. 2-Buten-1,4-diol (14) 30.0 g (340 mmol) was added to the mixture, where benzyl chloride 94.8 g (743 mmol) was added dropwise at 80 ± 15 CC. The mixture was stirred at the same temperature for 2 hours. The reaction mixture was cooled, and separated after the addition of 90 ml of water. Acidified brine with sulfuric acid was added to the organic layer. The solution was neutralized with aqueous sodium bicarbonate, separated, mixed with ethyl acetate and concentrated under reduced pressure to yield the residual oil 104.5 g (quantitative) of the objective (15). 1 H-NMR (CDCL3-TMS) d ppm: 4.05 (d, J = 3.8 Hz, 2H), 4.48 (s, 2H), 5.78 (m, 2H), 7.31 (m, 10H). / Benzyloxyethoaldehyde (16) 16 1458 My 1,4-dibenzyloxy-2-butene (15) 104.5 g (340 mmol) obtained above was dissolved in methanol. The solution was cooled to -60 ° C under nitrogen atmosphere. Ozone was introduced at -60 ° C until the initial materials dissipated, and then the excess ozone was removed by bubbling with nitrogen gas. Triphenylphosphine ethyl acetate 107.2 g (409 mmol) was added dropwise at -60 ° C to reduce the intermediate of the reaction. The reaction mixture was warmed to room temperature, and concentrated under reduced pressure to yield the oily mixture 321.6 g (quantitative) of the phosphorus compound and the objective (16).

(III) 2-Benzyloxymethyl-4-isopropyl-1H-imidazole (17) 268 g (approximately 0.57 mol) of the oily residue obtained in (II) of benzyloxyacetaldehyde (16) and the extract 183 g (0.70 mol) obtained in (I) of 2, 2-dichloro-3-methylbutylaldehyde (13) were obtained. mixed with 276 ml of acetonitrile. 25% was added to this aqueous ammonia. The mixture was stirred at 45 ° C for 8 hours, extracted with 213 ml of toluene and separated to yield 725 g of the extract (yield 70%) of the objective (17). The compound (17) can be crystallized with hexane.

XH-NMR (CDCL3-TMS) d ppm: 1.23 (d, J = 6.8 Hz, 6H), 2.88 (sept, J = 6.8 Hz, ÍH), 4.51 (s, 2H), 4.58 (s, 2H), 6.65 (d, J = 1.0 Hz, 1H), 7.1-7.4 (m, 5H).

(IV) 4-chloromethoxy-lyridine hydrochloride (19. 18 19 4-Hydroxymethylpyridine (18) 54.4g (0.50 mol) was dissolved in 202 ml of acetonitrile. The solution was added dropwise to the mixture of 65.3 g (0.55 mol) of thionyl chloride and 109 ml of acetonitrile under 50 ° C. The mixture was stirred at the same temperature for 1 hour, then cooled to room temperature to produce the (quantitative) suspension of the objective (19). 1 H-NMR (DMSO-TMS) d ppm: 5.09 (s, 2H), 8.09 (d, J = 6.6 Hz, 2H), 8.94 (d, J = 6.6 Hz, 2H).

(V) 2 Nitrate of 2-l-genzyloxymethyl-4-isopropyl-1- (pyridin-4-yl) met il-lH-imidazole (20) The extract was neutralized with 725 g (approximately 0.40 mol) obtained in (III) of 2-benzyloxymethyl-4-isopropyl-1H-imidazole (17) mixed with the suspension (approximately 0.50 mol) obtained in (IV) of 4-chloromethylpyridine hydrochloride (19) and water, and basified by aqueous sodium hydroxide. The mixture was separated, the aqueous layer was extracted with 65 ml toluene and the organic layer was collected. The organic layer was concentrated to 830 ml, mixed with 62.6 g sodium hydroxide, and stirred at 40 ° C for 5 hours. The reaction mixture was mixed with water 226 ml and separated. The aqueous layer was extracted with 65 ml toluene and the organic layer was collected. The organic layer was mixed with 348 g of 20% aqueous sulfuric acid and the aqueous layer was separated. The organic layer was extracted with 65 ml water, and the aqueous layer was collected. The aqueous layer was mixed with 282 g 20% aqueous sodium hydroxide and extracted with 130 ml of ethyl acetate. The organic layer was washed with brine, and each of the aqueous layers was extracted with 65 ml of ethyl acetate. The organic layer was collected, concentrated under reduced pressure and dried. The residue was mixed with 523 ml of ethyl acetate and 131 ml of methanol, crystallized with concentrated sulfuric acid 82.9 g (0.89 mol), filtered and dried to yield the objective (20) 161.3 g of a pale yellow crystal. Performance 90%. P.f. 155 ° C (dec).

The objective compound (20) can be crystallized with isopropyl ether. 2H-NMR (CD3OD-TMS) 6 ppm: 1.34 (d, J = 7.0 Hz, 6H), 3.08 (sept, J = 7.0 Hz, 1H), 4.86 (s, 2H), 4.89 (s, 2H), 5.78 (s, 2H), 7.16 (m, 2H) 7. 28 (m, 2H), 7.49 (d, J = 1.0 Hz, ÍH), 7.74 (d, J = 6.8 Hz, 2H), 8.67 (d, J = 6.8 Hz, 2H). 2-Benzyloxy-ethyl-5- (3,5-dichlorophenylthio) -4-isopropyl-1- (pyridin-4-yl) met i 1-1H-imidazole (5) 50 ml of toluene and 12 ml of water were suspended in 2 ml of 2-benzyloxymethyl-4-isopropyl-1- (pyridin-4-yl) -1H-imidazole nitrate (20) 13.9 g (31 mmol). The solution was neutralized with. 30% aqueous sodium hydroxide. The toluene layer was washed with 40 ml of water, concentrated and dried. The residue was dissolved in 50 ml of toluene. The solution was added dropwise to 24.7 g of the toluene solution with 7.9 g (37 mmol) of 3,5-dichlorobenzenesulfenyl chloride (2). 3.5 g (34 mmol) of triethylamine was added to the mixture in the form of drops under ice cooling for 1 hour. The mixture was stirred at the same temperature for 2.5 hours, and mixed with 25 ml of water. The toluene layer was separated and washed with 25 ml of water, and the aqueous layer was extracted with 10 ml of toluene. The toluene layer was collected and concentrated under reduced pressure. The residue was crystallized with isopropyl ether, filtered and dried to yield the objective (5) 13.0 grams of a pale yellow crystal. Performance 84%. 1H-NMR (CDC13) d ppm: 1.30 (d, J == 7.2 Hz, 6H), 3.08-3.22 (, ÍH), 4.52 (s, 2H), 4.62 (s, 2H), 5.16 (s, 2H) , 6.65 (d, J = 1.8 Hz, 2H), 6.79 (d, J = 6.0 Hz, 2H), 7.03 (t, J = 1.8 Hz, ÍH), 7.18-7-36 (, 5H), 8.38 (d , J = 6.0 Hz, 2H). 2-hydroxymethyl-5- (3,5-dichlorophenylthio) -4-isopropyl-1- (pyridin-4-yl) ethyl-1H-imidazole (9 Aqueous concentrated hydrochloric acid 50 ml was added to the compound (5). The mixture was heated at 90 ° C for 2 hours and then cooled. 50 ml of water and 20 ml of toluene were added to the mixture. The aqueous layer was separated and neutralized with 30% aqueous sodium hydroxide. The compound (9) was extracted with 50 ml of ethyl acetate, and the ethyl acetate layer was • washed with 30 ml of water. The aqueous layer was extracted with 20 ml of ethyl acetate. The ethyl acetate layer was collected and concentrated under reduced pressure to yield the oily residue. 50 ml of isopropyl ether was slowly added to the oily residue. The suspension obtained was stirred at room temperature for 30 minutes, filtered, washed with 30 ml of isopropyl ether, and dried to yield compound (9) 10.4 g as a white crystal.

Compound yield (20): 82% 2-carbamoyloxymethyl-5- (3,5-dichlorophenylthio) 4-isoproyl-l- (pyridin-4-yl) methyl-lH-imidazole (11) eleven The hydroxy compound (9) 2.00 g (4.9 mmol) was suspended in 20 ml of ethyl acetate, and the solution was cooled to -30 ° C under a nitrogen atmosphere. A solution of 1.66 g (11.4 mmol) of chlorsulfonyl isocyanate was added dropwise to the solution under a nitrogen atmosphere at -30 ° C for 30 minutes, and the mixture was stirred at the same temperature for 1 hour. 2 ml of water were added to the mixture as drops, and the mixture was heated to 0 ° C. 2 ml of 35% aqueous hydrochloric acid and 4 ml of methanol were added to the mixture, and the solution was stirred at 40 ° C for 1 hour. The mixture was cooled to room temperature and neutralized with 20% aqueous sodium carbonate. The organic layer was separated, washed with water, concentrated and dried. 6 ml of methanol were added to the residue and then 6 ml of water at room temperature. The suspension obtained was filtered, washed with 6 ml of 50% aqueous methanol, and dried to yield compound (11) 2.06 g (yield 93.2%). XH-NMR (CDCI3-TMS) d ppm: 1.32 (d, J = 6.9 Hz, 6H), 3.17 (sept, 1H), 4.53 (b, 2H), 5.21 (s, 2H), 5.27 (s, 2H) , 6.69 (d, J = 1.6 Hz, 2H), 6.82 (d, J = 5.2 Hz, 2H), 7.06 (t, J = 1.6 Hz, ÍH), 8.46 (b, 2H).

Analysis of Elements (C2oH2oCl2N4? 2S • 0.5H2O) (%) Cale: C, 52.16: H, 4.61: N, 12.17: S, 6.96: Cl, 15.42 (%) found: C, 52.45: H, 4.72: N, 11.73: S, 7.08: Cl, 14.81 Salt of the compound (11) 2HC1: p. F. 214-222 ° C (dec) Examples 5-6 The compounds created in the same manner as described above were produced with the established reaction conditions.

Table 1 Table 2 INDUSTRIAL APPLICABILITY The present invention provides a process for the production of imidazole (III) derivatives useful as an antiviral agent and an anti-HIV agent. Which is conveniently applicable, for large-scale economic production.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (6)

1. A process for producing a compound of the formula (III), wherein: where RJ R are independently hydrogen or an organic group; R: it is an organic group; and R4 is an optionally substituted aryl, characterized Doraue corriDrende noner to react a compound of the formula (I): R1 I (i) N Where R1, R2 and R3 are as defined above, with a compound of the formula (II): R4-S-Hal (II) where R is as defined above and Hal is halogen, in the presence of a base.
2. 2. The process as claimed in claim 1, characterized in that the organic group is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, an optionally substituted arylthio, an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl, an optionally substituted aralkyl , an optionally substituted acyl, an optionally substituted carbamoyl, an optionally substituted alkoxycarbonyl, -CH = N0H, -CH = NNH2, or -AX where A is -CH20CH2- or -CH20- and X is an optionally substituted aryl, or -COR5 where R5 is an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted aryl, or an optionally substituted amino.
3. 3. The process as claimed in claim 1 or 2, characterized in that the process wherein R1 is hydrogen or an optionally substituted heteroalkyl; R2 is -A-X where A is -CH2OCH2- or -CH20- and X is an optionally substituted aryl, or -COR5 wherein R5 is an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted aryl, or an optionally substituted amino; and R3 is an optionally substituted alkyl.
4. 4. The process as claimed in any of claims 1-3, characterized in that R1 is an optionally substituted pyridimethyl.
5. 5. The process as claimed in any of claims 1-4, characterized in that a compound of the formula (II) is 3,5-dichlorobenzenesulfenyl chloride.
6. 6. The process as claimed in any of claims 1-5, characterized in that the base is triethylamine or N-methylmorpholine. SUMMARY OF THE INVENTION The present invention provides a process for producing a compound of the formula (III): wherein R1 and R3 are independently hydrogen or an organic group; R2 is an organic group; and R4 is an optionally substituted aryl, reacting a compound of the formula (I): ir (i) Where R1, R2 and R3 are as defined above, with a compound of the formula (II): R4-S-Hal (II Where R is as defined above and Hal is halogen, in the presence of a base.