MXPA00009915A - Process for producing arylsulfenyl halide - Google Patents

Abstract

A process for producing a compound represented by formula (I) which comprises reacting a compound represented by formula (V) with a compound represented by formula (VI) in the presence of a base;a process for producing a compound represented by formula (II) which comprises causing a halogenating agent to act on the compound represented by formula (I);a process for producing a compound represented by formula (IV) which comprises reacting the compound represented by formula (II) with a compound represented by formula (III);and the compound represented by formula (I), wherein Alk represents branched alkyl;Hal1 and Hal2 each represents halogeno;R1 and R2 each independently represents halogeno, alkyl, alkoxy, nitro, and cyano;R3 and R5 each represents hydrogen or an organic residue;and R4 represents an organic residue.

Description

DESCRIPTION Process to produce arylsulfenyl halide TECHNICAL FIELD This invention relates to a process for producing arylsphenyl halide and a precursor thereof, alkyl aryl sulphide, which are useful as starting materials for a medicament, especially an antiviral agent or an agent for the treatment of AIDS.

BACKGROUND OF THE INVENTION A compound of the formula (IV): where R1 and R2 each independently represent halogen, alkyl, alkoxide, nitro or cyano, R3 represents hydrogen or an organic residue, R4 represents an organic residue and R5 represents hydrogen or an organic residue, it is known to be pharmacologically active, useful as an antiviral agent or an agent for the treatment of AIDS (WO 96/10019). REF .: 123213 In WO 96/10019 the compound of the formula (IV) prepared by the condensation of the thiophenol or disulfide derivatives and 4-halogenoimidazole is disclosed. However, this reaction requires the use of a strong base such as lithium hydride, sodium hydride or potassium hydride. In addition, the reaction must be carried out under heating because it does not proceed at room temperature. This reaction is, therefore, inappropriate for the industrial process.

We have already filed an application concerning a new synthetic route for the stable support of the compound of the formula (IV) (PCT / JP97 / 04708). It is necessary to establish a process for producing a compound of formula (II): where Hal1 represents the halogen and R1 and R2 are as defined above, one of the starting materials used in the new synthetic route, which is applicable to a convenient, economical and large-scale production.

Otherwise, some processes for producing a compound similar to that of the formula (II) of the present invention have been known. Usually the process used to produce the arylsulfenyl halide is a process which comprises allowing a halogenating agent to react with a disulfide derivative prepared by the oxidation of an aromatic thiol derivative. The process for repairing the disulfide derivative from the aromatic thiol derivative has been described in, for example, Chem. Ind., 501 (1964), Synte4sis-stuttgart, (5), 378-380 (1989), J. Organomet. Chem., 368 (3), 295-302 (1989) and Tetrahedron Letter, 31 (35), 5007-5010 (1990). The process comprising allowing the halogenating agent to react with the disulfide derivative which has been described in, for example, Org. Synth., II 455, (1943).

Another known method is the process comprising allowing the halogenating agent to react with the substituted sulfur derivative with benzyl or the like which is prepared from the aromatic thiol derivative. The process for preparing the sulfide derivatives substituted with benzyl or the like from the aromatic thiol derivatives have been described in, for example J. Org. Chem., 42 (26), 4275 (1977), Tetrahedron Letter, 635, (1969) and Chem. Pharm. Bull., 40 (8), 1986-1989 (1992). The process comprising allowing the halogenating agent to react with sulfur derivatives substituted with benzyl or the like have been described in, for example J. Org. Chem., 28, 1903 (1963). These conventional methods, however, require many steps to prepare starting materials, disulfide derivatives and sulfur derivatives. Waste such as benzyl and the like are generally expensive and inappropriate for the industrial process.

Some processes for producing the aromatic thiol derivatives which are the starting materials of the disulfide derivatives mentioned above and the sulfide derivatives have been known. Examples of the processes include the method comprising allowing the sulfide to react with the Grignard reagent prepared from the corresponding commercially available halide (Chem. Ver., 72, 594 (1939)), the method comprises preparing the xanthate from the lysozy intermediates prepared from the corresponding commercially available aniline derivatives and hydrolyzing in the next step. (Org Synth. Coll., Vol. 3, 809 (1955)), the method of thermal rearrangement of thiourethane prepared by the acylation of readily available phenol derivatives and further hydrolysis (J. Org. Chem., Vol. 31, 3980 (1966)), and the chlorination of methylmerite derivatives prepared by the substitution reaction of methyl ercaptan with the corresponding halide and further hydrolysis (JP-A 9-40636).

These methods are, however, inappropriate for the industrial process because they not only require many steps but also proceed via unstable intermediates such as Grinnard reagents and diazo derivatives. Indeed, these methods are difficult to apply for the industrial process because the arylsulfenyl halide obtained is expensive.

Examples of the other synthetic methods concerning the arylsulfenyl halide include the process for producing the arylsu phenyl halide which comprises allowing the halogenating agent to react with the alkyl aryl sulfide derivatives prepared from the halogenated benzene derivatives.

As the process for producing the alkyl aryl sulphide, the process for producing 2,5-dichlorophenylalkylsulfide from 1,2-trichlorobenzene was disclosed in JP. A 9-56760. In Tetrahedron Letters, 1982, 23, 4629, the process for producing 4-chlorophenylalkylsulfide from 1,4-dichlorobenzene was disclosed.

As the process for producing the arylsphenyl halide from the alkylarylsulfide, the process for producing 4-isopropoxyphenylsuiphenylhalide from sulfur isopropyl 4-isopropoxyphenyl was disclosed (Synthesis, 1976, 451).

These literatures and the like do not reveal the process described above using the 3, 5-dihalogenated benzene derivatives as starting materials. In J. Org. Chem., 1980, 45, 3880-3884, 3,5-dichlorophenylsufenylchloride was disclosed, but a process thereof is not fully mentioned.

DISCLOSURE OF THE INVENTION The present inventors have intensively studied the process for producing the arylsulfenyl halide, which is applicable to a convenient, economical and large-scale production and have found the process to efficiently produce the compound of the formula (II) with few Steps under mild condition, which comprises reacting the compound of the formula (V) with the compound of the formula (VI) in the presence of a base, followed by the reaction with a halogenating agent, to carry out the present invention. In addition, the compound of the formula (IV) has been prepared through the reaction of the compound of the formula (II) obtained above with the compound of the formula (III); (VI) (I) (H) (IV), where Alk represents the branched alkyl, and each Hal independently represents the halogen, each R1 and R2 independently represents the halogen, alkyl, alkoxy, nitro or cyano, each R3 and R5 independently represents hydrogen or an organic residue and R4 represents an organic waste.

BEST MODE FOR CARRYING OUT THE INVENTION Preferred embodiments are shown below, The present invention provides; (1) a process for producing a compound of formula (II): where Hal1 represents the halogen and each R1 and R2 independently represents the halogen, alkyl, alkoxide, nitro or cyano, which comprises allowing the halogenating agent to react with a compound of the formula (I): wherein Alk represents the branched alkyl and R1 and R2 are as defined above.

In addition, the present invention provides; (2) a process for producing a compound of the formula (IV): (IV) wherein R1 and R2 are as defined above, R3 represents hydrogen or an organic residue, R4 represents an organic residue and R5 represents hydrogen or an organic residue, which comprises preparing a compound of formula (II): where Hal1 represents the halogen and R1 and R2 are as defined above, by the process mentioned above, after reacting the compound of the formula (II) with a compound of the formula (III) where R3, R4 R ° are as defined above, Additionally, the present invention provides; (3) a process for producing a compound of the formula (I): wherein Alk, R1 and R2 are as defined above, which comprises reacting a compound of the formula (V) Al -SH (V) Where Alk represents as defined above, With a compound of the formula (VI): where Hal2 represents the halogen and R1 and R2 are as defined above, in the presence of a base.

In addition, the present invention provides; (4) a process for producing a compound of formula (II): wherein Hal1, R1 and R2 are as defined above, which comprises preparing a compound of formula (I): wherein Alk, R1 and R2 are as defined above, by the process mentioned above, after allowing the halogenating agent to react with the compound of formula (I).

In addition, the present invention provides; (5) a process for producing a compound of the formula (IV): (IV) wherein R1, R2, R3, R4 and R5 are as defined above, which comprises preparing a compound of formula (II): where Hal1 represents the halogen and R1 and R2 are as defined above, by the aforementioned process, after reacting the compound of the formula (II) with a compound of the formula (III): where R3, R4 and R5 are as defined above.

In the process (1) or (4) mentioned above, . Chlorine is preferred as the halogenating agent.

In (3) mentioned above, it is preferred to react in the presence of a phase transfer catalyst. Additionally, the quaternary ammonium salt or a quaternary salt of the phosphonium is preferred as a phase transfer catalyst.

In process (1) or (3) mentioned above, isopropyl or tert-butyl is preferred as alk.

In any of one of the processes (1) - (5) mentioned above, the process wherein each R1 and R2 independently represent the halogen is preferred.

In (2) or (5) mentioned above, the process wherein R3 represents hydrogen or optionally substituted heteroarylalkyl, R4 represents -AX where A represents -CH2OCH2- OR -CH20-, X optionally represents the substituted aryl or -COB where B optionally represents the substituted alkyl, optionally the substituted alkoxide, optionally the substituted aryl or optionally the substituted amino and R5 optionally represents the substituted alkyl. Especially, the process is preferred where R3 optionally represents the substituted pyridylmethyl.

In addition, the present invention supplies the intermediate of the formula (la): wherein each Ru and R21 independently represents the halogen, alkyl, nitro or cyano and Alk is as defined above. Especially, the compound is preferred wherein each R 11 and R 12 independently represents the halogen.

The term "an organic residue" in the present specification includes optionally substituted alkyl, optionally substituted alkenyl, • optionally substituted aryl, optionally substituted arylthio, optionally substituted hereoaryl, optionally substituted heteroarylalkyl, optionally substituted aralkyl, optionally substituted acyl, optionally substituted carbamoyl, optionally substituted alkoxide, optionally substituted alkoxycarbonyl, halogen, -CH = NOH, -CH = NNH2, optionally substituted aralkyloxyalkyl, optionally substituted aryloxyalkyl, optionally substituted acylalkyloxyalkyl, optionally substituted acyloxyalkyl, optionally substituted alkoxycarbonylalkyloxyalkyl, optionally substituted alkoxycarbonyloxyalkyl, optionally substituted carbamoylalkyloxyalkyl, optionally carbamoyloxyalkyl replaced and the like.

The term "alkyl" by itself or as a part of (a) another substitute (s) means straight or branched C?-C2o alkyl, which includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. Especially, lower alkyl Ci-Cß is preferred.

The term "branched alkyl" includes the C3-Cs branched alkyl, such as isopropyl, isobutyl, tert-butyl, isopentyl, and the like. Especially, isopropyl or tert-butyl is preferred.

The term "alkoxide" by itself or as a part of (a) substitute (s) means alkyloxide, which includes the methoxide, ethoxide, propoxide or tert-butoxide.

The term "alkenylp" includes straight or branched C2-C20 alkenyl, such as vinyl, allyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl and the like.

Especially, C2-C7 lower alkenyl is preferred. The term "aril" by itself or as a part of (a) other substitute (s) means the aromatic carbocyclic group, which includes phenyl, naphthyl and the like.

Examples of the "optionally substituted aryl" include phenyl, 3,5-dichlorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3,5-dimethoxyphenyl, 2,4,6-trimethylphenyl, 3, 5-di-tert-butylphenyl, 4-methoxyphenyl, 4-benzylphenyl, 4-hydroxyphenyl, 3, 5-dinitrophenyl, 3-nitrophenyl, 3, 5-diaminophenyl, 3-aminophenyl, naphthyl and the like.

The term "arylthio" includes phenylthio • naftiltio.

The term "heteroaryl" by itself or as a part of (a) other substitute (s) means the 5- to 7-membered heterocyclic group containing at least one hetero atom (N, 0 or S), which includes pyridyl ( for example, 4-pyridyl), pri idinyl (for example, 2-pyrimidinyl), pyridazinyl (for example, 3-pyridazinyl), pyrazinyl (for example, 2-pyrazinyl), thienyl (for example, 2-thienyl), quinolyl (e.g., 3-quinolyl), imidazolyl (e.g., 2-imidazolyl), oxalyl (e.g., 2-oxalyl), thiazolyl (e.g., 5-thiazolyl), and the like. Especially, pyridyl is preferred.

The term "heteroarylalkyl" includes pyridyl ethyl (e.g., 4-pyridylmethyl), pyridylethyl (e.g., 1- (2-pyridyl) ethyl or 2- (2-pyridyl) ethyl), pyridylpropyl (e.g., 3- ( 2-pyridyl) propyl), thienylmethyl (for example, 2-thienylmethyl), quinolylmethyl (for example, 3-quinolylmethyl), imidazolylmethyl (for example, 2-imidazolylmethyl) and the like.

The term "aralkyl" by itself or as a part of (a) another substitute (s) means arylalkyl, which includes benzyl, phenethyl (eg, 1-phenethyl), naphthylmethyl, naphthylethyl (eg, 2-naphthylethyl) and the similar ones.

The term "acyl" by itself or as a part of (a) other substitute (s) means alkylcarbonyl or arylcarbonyl, which includes acetyl, propionyl, pivaloyl, benzoyl and the like.

The term "optionally substituted carbamoyl" includes unsubstituted carbamoyl or the mono- or disubstituted carbamoyl, such as carbamoyl, N-methylcarbamoyl, N, N, -dimethylcarbamoyl and the like.

The term "alkoxycarbonyl" includes methoxycarbonyl, ethoxycarbonyl and the like.

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

The term "optionally substituted amino" means unsubstituted amino or mono- or disubstituted amino, which includes amino, methylamino, dimethylamino and the like.

The term "aralkyloxyalkyl" includes benzyloxymethyl, benzyloxyethyl, phenethyloxymethyl (e.g., 1-phenethyloxymethyl) and the like.

The term "aryloxyalkyl" includes phenyloxymethyl, phenyloxyethyl, 3,5-dichlorophenyloxymethyl and the like.

The term "acylalkyloxyalkyl" includes acetylmethyloxymethyl, acetylmethyloxyethyl, propionylethyloxyethyl, benzomethyloxymethyl, benzoethyloxymethyl, benzomethyloxyethyl and the like.

The term "acyloxyalkyl" includes acetyloxymethyl, acetyloxyethyl, propionyloxymethyl, benzoyloxymethyl, benzoylethyl and the like.

The term "alkoxycarbonylalkyloxyalkyl" includes methoxycarbonylmethyloxymethyl, methoxycarbonylethyloxymethyl and the like.

The term "alkoxycarbonyloxyalkyl" includes methoxycarbonyloxymethyl, methoxycarbonyloxyethyl and the like.

The term "optionally substituted carbamoylalkyloxyalkyl" includes carbamoylmethyloxymethyl, carbamoylmethyloxyethyl, carbamoylethyloxymethyl, N-methylcarbamoylmethyloxymethyl, N, N, -dimethylcarbamoylmethyloxymethyl and the like.

The term "carbamoyloxyalkyl" includes carmoyloxymethyl, carbamoylethyl, N-methylcarbamoyloxymethyl, N, N-dimethylcarbamoyloxymethyl and the like. When each group described above is substituted, the substituent refers to, for example, alkyl (eg, methyl, ethyl), halogen (fluorine, chlorine, bromine, iodine), acyl (eg, acetyl, benzoyl), alkenyl ( for example, allilo), cycloalkyl (for example, cyclopropyl), aralkyl (for example, benzyl), optionally substituted amino (for example, methyl amino, dimethylamino) hydroxide, oxo, alkoxide (for example, methoxide, .ethoxide), cyano , carbonyl, alkoxycarbonyl (e.g., methoxycarbonyl), nitro, acyloxide (e.g., acetyl oxide), optionally substituted carbabonyl (e.g., methoxycarbanoyl), nitro, acyloxide (e.g., acetyloxido), optionally substituted carbamoyl (e.g., N- methylcarbamoyl), optionally substituted carbamoyloxide (N-ethylcarbamoyloxide) and the like.

One or more substitute (s) can be in any substitutable position (s). When the substitute interferes in the reaction, a protecting group can be introduced before the reaction, and after being removed at any suitable step after the reaction.

The examples of the present invention are shown below.

(VI) (I) (H) where Alk, Hal1 Hal2, R1, R2 R3, R4 and R5 are as defined above.

(PROCESS 1) This process is the process for producing the compound of formula (I), which comprises reacting the compound of formula (V) with the compound of formula (VI) in the presence of a base.

The compound of formula (V) includes commercially available isopropyl mercaptan and tert-butyl mercaptan. The compound of the formula (VI) may be commercially available or prepared according to the general procedure, which includes, for example, 1,3,5-trichlorobenzene, 1, 3, 5, -tribromobenzene, 1-bromo-3, 5 , - dichlorobenzene, 1,3-dibromo-5-chlorobenzene, l-chloro-3,5-dibro-benzene, l-chloro-3,5-dimethylbenzene, l-bromo-3,5-dimethoxybenzene, 1,3-dichloro -5-nitrobenzene, l-chloro-3,5-dicyanobenzene, l-chloro-3-methyl-5-nitrobenzene, l-nitro-3,5-dichlorobenzene and the like. Especially, l-bromo-3,5-dichlorobenzene or 1, 3, 5-trichlorobenzene is preferred.

The compound of the formula (V) in the gaseous state or liquid state can be added to an aqueous alkaline solution, to prepare a solution containing the salt of the compound of the formula (V), or the compound of the formula (V) in the gaseous state or liquid state it can be directly added to the reaction mixture prepared with base and water. In this process, the amount of the compound of the formula (V) is usually from 0.5 to 5.0 mol equivalents, preferably from 1.0 to 1.5 mol equivalents to the compound of the formula (VI). The reaction temperature can be from 0 to 200 ° C, preferably from 25 to 140 ° C.

The base used includes the alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and the like; alkali metal carbonate such as sodium carbonate, potassium carbonate and the like. Especially, potassium hydroxide is preferred. The amount of the base is usually from 0.5 to 2.0 mole equivalents, preferably from 1.0 to 1.2 mole equivalents to the compound of the formula (V).

The solvent used is water, the solvent mixed to two phases that comprises water and the organic solvent not miscible with water, or organic solvent. In the case of the solvent was the water, the aqueous solution containing the salt of the compound of the formula (V) can be prepared in advance as shown above. The organic solvent immiscible with water includes, is not limited to, the cyclohexane, methylcyclohexane, benzene, toluene, xylene, monochlorobenzene, dichlorobenzene, and the like. In the case of mixed solvent comprising water and organic solvent not miscible with water, the amount of the organic solvent immiscible with water is 0.5 to 5.0 equivalent weight, preferably 1.0 to 2.0 equivalent step for water. The compound of the formula (VI) by itself, for example, 1, 3, 5-trichlorobenzene, can be used as an organic solvent not miscible with water. In this case, the reaction is carried out in the solvent mixed in two phases in that 1,3,5-trichlorobenzene is the organic solvent not miscible with water. The addition of the phase transfer catalyst is preferred to easily carry out the reaction. The phase transfer catalyst can be used even in the quaternary ammonium salt such as tetraethylammonium bromide, tetraethylammonium chloride, tetra-n-propylammonium bromide, tetra-n-propylammonium chloride, tetra-n-pentylammonium bromide, tetra-n-pentylammonium chloride, tetra- n-hexylammoniobromide, tetra-n-hexylammonium chloride, tetra-n-heptylammonium bromide, tetra-n-heptylammonium chloride, tetra-n-octylammonium bromide, tetra-n-octylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium chloride and the like; the phosphorus ammonium quaternary salt such as tetraethylphosphorobromide, tetraethylphosphorochloride, tetra-n-propylphosphorobromide, tetra-n-propylphosphorobromide, tetra-n-butylphosphorochloride, tetra-n-butylphosphorochloride, tetra-n-pentylphosphorobromide, tetra-n-pentylphosphorochloride, tetra-n-hexylphosphorobromide, tetra-n-hexylphosphorochloride, tetra-n-heptylphosphorobromide, tetra-n-heptylphosphorochloride, tetra-n-octylphosphorabide, tetra-n-octylphosphorochloride, tetraphenylphosphorobromide, tetraphenylphosphorochloride and the like. In particular, the preferred quaternary ammonium salt is tetra-n-butylammonium bromide, tetra-n-butylammonium chloride and the like. The amount of the catalyst is usually from 0.01 to 1.0 mol equivalents to the compound of the formula (VI). This catalyst can be used by itself or as the combination of two or more quaternary ammonium salts, two or more quaternary phosphonium salts, or quaternary ammonium salts and quaternary phosphorus salts.

In the case that the organic solvent can be used by itself, the polar solvent such as hexamethylphosphorotriamide, dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, can be used, N, N, dimethylacetamide and the like. Especially, hexamethylphosphorotriamide, is preferred.

(PROCESS 2) This process is the process for producing the compound of formula (II), which comprises allowing the halogenating agent to react with the compound of formula (I) • The halogenating agent includes the chlorinating agent such as chlorine sulfuryl chloride, N-chlorosuccinimide and the like, the bromination agent, such as bromine, N-bromosuccinimide and the like or iodine. Especially, chlorine or bromine is preferred. The amount of the halogenating agent is 1.0 to 10 mol equivalents, preferably 3.0 to 5.0 mol equivalents of the compound of the formula (I).

The solvent used includes, is not limited to, hydrocarbons such as hexane, cyclohexane, heptane and the like, the halogenated hydrocarbon such as dichloroethane, dichloromethane, chloroform, trichloromethane, carbon tetrachloride and the like, aromatic hydrocarbons such as benzene , toluene, xylene, chlorobenzene, dichlorobenzene, trichlorobenzene and the like. When the solvent was used, the amount of the solvent is, is not limited to, 1 to 1000 equivalent weight to the compound of the formula (I), The reaction mixture is from -10 to 50 ° C, preferably from 0 to 20 ° C.

(PROCESS 3) This process is the process for producing the compound of the formula (II) With a compound of the formula (III) • Some of the compounds of the formula (III) are known, which can be prepared according to the process WO96 / 10019 and JP-A 6-116242. The compound of the formula (III) used in the present invention includes 2-benzyloxymethyl-isopropyl-1H-imidazole, 2-benzyloxymethyl-4-isopropyl-1- (pyridin-4-yl) methyl-1H-imidazole, 2- acetyloxymethyl-4-isopropyl-1- (pyridin-4-yl) methyl-1H-imidazole, 2-benzoyloxymethyl-4-isopropyl-1- (pyridin-4-yl) methyl-1H-yl idazole, 2-methoxycarbonyloxymethyl-4 isopropyl-1- (pyridin-4-yl) methyl-lH-imidazole, 2-carbamoyloxymethyl-4-isopropyl-1- (pyridin-4-yl) methyl-1H-imidazole and the like, especially 2-carbamoyloxymethyl- 4-isopropyl-1- (pyridin-4-yl) methyl-1H-imidazole is preferred.

The base used includes triethylamine, N-methylmorpholine, pyridine, N, N-dimethylaniline, N, N-diisopropyl-N-ethylamine, butyl lithium, diazabicycloundecene and the like. The solvent used includes acetonitrile, toluene, methylene chloride, chloroform, dimethylformamide, nitromethane, benzene, tetrahydrofuran and the like.

In this process, the amount of the base is 0.1 to 3.0 mol equivalents, preferably 1.0 to 2.0 mol equivalents to the compound of the formula (III).

The amount of the compound of the formula (II) is 1.0 to 3.0 mol equivalents, preferably 1.0 to 2.0 mol equivalents to the compound of the formula (II). The reaction temperature is from -30 to 60 ° C, preferably from 0 to 10 ° C. The compound of the formula (II) can be added under stirring with the compound of the formula (III), and vice versa. The base can be mixed with the compound of the formula (III) anticipated, or it can be added in the end.

The following examples are provided to encourage illustration of the present invention and are not constructed as limits of the scope thereof.

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

I methyl Pr1 isopropyl Bu1"tert-butyl Bn Benzyl Ph phenyl HMPT triamide hexamethyl phosphorus TEA triethylamine DMF dimethylformamide Example 1 3, 5-Dichlorophenyl-Sod Pilsulfurc (2) B) i-PrSNa in HMPT Method A To a solution of 4 N sodium hydroxide (0.8 ml) was added isopropyl mercaptan (0.33 ml). The mixture was stirred for 10 minutes at room temperature. 1,3,5-trichlorobenzene (1) (1.8 g, 10 mmol) and tetra n-butylammoniobromide (322 mg, 1 mmol) were added thereto. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with water, dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was chromatographed twice with silica gel (Si02 18 g, elution: n-hexane) to yield objective (2) (566 mg). Performance 85%. IR (film) 1555, 1375, 1360, 1155 cm "1 .1H-NMR (CDC13, 200MHZ) d: 1.32 (6H, d, J = 6.4Hz), 3.42 1H, sept, J = 6.4Hz), 7.15- 7.25 (3H, m).

Method B To a solution of hydride: sodium (120 mg, 3 mmol, in oil, 60% cont.) In anhydrous methanol (5 ml) was added isopropylmercaptan (0.335 ml). The mixture was stirred for 10 minutes at room temperature. The reaction mixture was concentrated without moisture under reduced pressure and dried. The sodium isopropyl mercaptan obtained was dissolved in HMPT 82 ML), 1, 3, 5-trichlorobenzene (1) (1.8 g, 10 mmol) was added thereto. The mixture was stirred for 2.5 hours at 80 ° C. The reaction mixture was stirred in ice water. The mixture was extracted with ethyl acetate, washed with water, dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was chromatographed twice with silica gel (Si02 25 g, elution: n-hexane) to yield the objective (2) (475 mg). Performance 71%.

Example 2 2-Benzyloxymethyl-5- (3,5-dichlorophenylthio) -4-isopropyl-1- (pyridin-4-yl) methyl-1H-imidazole (6) To the solution of compound (2) (221 mg, 1 mmol) prepared in Example 1 in carbon tetrachloride (1 ml) was added chlorine (0.7 mol / 1 in carbon tetrachloride, 5.6 ml) under stirring and a cooling with ice. The reaction mixture was stirred at the same temperature for 3.5 hours. The solvent was removed under reduced pressure, and the excess of. Chlorine was removed too. The concentrated residue was dissolved in toluene (5 ml). Compound (5) (prepared according to Reference Example 1 of WO96 / 10019) (321 mg) and N-methyl morpholine (0.24 ml) were added while cooling with ice thereto. The mixture was allowed to arrive overnight at room temperature. The mixture was poured into ice water containing sodium bicarbonate, extracted with ethyl acetate, washed with water, dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was chromatographed with silica gel Si02 15 g, elution. Toluene-ethyl acetate 1: 1 to ethyl acetate) to yield the objective (6) (186 mg) as the first fraction and the unreacted compound (5) (162 mg) as the second fraction. Yield of compound (6) to compound (2): 38 Example 3 3, 5-Dicl-phenyl-tert-butylsulfide () B) t-BuSNa in HMPT Method A To a solution of 4 N sodium hydroxide (0.8 ml) was added tert-butyl mercaptan (0.406 ml). The mixture was stirred for 14 minutes at room temperature. The tetra-n-butylammonium bromide (322 mg, 1 mmol) and 1, 3, 5-trichlorobenzene (1) (1.8 g, 10 mmol) were added thereto. The reaction mixture was refluxed at 140 ° C for 6.5 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with water, dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was chromatographed twice with silica gel (Si02 15 g, elution: n-hexane = to yield the objective (4) (138 mg), yield 19%, IR (film) 1555, 1400, 1380, 1360 cm. "1. XH-NMR (CDC13, 200 MHz) d: 1.31 (9H, S), 7.34-7.44 (3H, m).

Method B To a solution of sodium hydroxide (120 mg, 3 mmol, in oil, 60% cont.) In anhydrous methanol (5 ml) was added tert-butyl mercaptan (0.4016 ml). The mixture was stirred for 20 minutes at room temperature. The reaction mixture was concentrated without moisture under reduced pressure. The sodium isopropylmercaptan was dissolved in HMPT (2 ml). 1, 3, 5-trichlorobenzene (1) (1.8 g, 10 mmol) was added thereto. The mixture was stirred for 2 hours and 50 minutes at 80 ° C. The reaction mixture was poured into ice water. The mixture was extracted with ethyl acetate, washed with water, dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was chromatographed twice with silica gel (Si02 15 mg, elution: n-hexane) to yield the objective (4) (293 mg). Performance 41%.

Example 4 2-Benzyloxymethyl-5- (3,5-dichlorophenylthio) -4-isopropyl-1- (pyridin-4-yl) methyl-1H-imidazole (6) To a solution of the compound (4) (235 mg, 1 mmol) prepared in Example 3 in carbon tetrachloride (1 ml) was added under a cooling with ice chlorine (0.7 mol / l in carbon tetrachloride)., 4.2 ml). The reaction mixture was stirred at the same temperature for 1.5 hours. The solvent was removed under reduced pressure, and the excess chlorine was removed as well. The concentrated residue was dissolved in toluene (5 ml). Compound (5) (prepared according to Reference Example 1 of WO96 / 10019) (321 mg, 1 mmol) and N-methyl morpholine (0.24 ml) were added under ice-cooling. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was allowed to arrive overnight at room temperature. The mixture was poured into ice water containing sodium bicarbonate, extracted with ethyl acetate, washed with water, dried with sodium sulfate and concentrated under reduced pressure. The obtained residue was chromatographed with silica gel (Si02 15 g, elution: toluene-ethylacetate 1: 1 to ethylacetate) to yield the objective (6) (233 mg) as the first fraction and the unreacted compound (5) ( 143 mg) as the second fraction. Yield of compound (6) to compound (4): 46 Example 5 2-Benzyloxymethyl-5- (3,5-dichlorophenylthio) -4-isopropyl-1H-imidazole (8) 8 2-Benzyloxymethyl-4-isopropyl-1H-imidazole (7) (550 mg, 2.4 mmol), described in Reference Example 1 of WO 96/10019 a mixture of triethylamine 360 mg (3.6 mmol) and acetonitrile 4 ml was dissolved. To a solution was added 3,5-dichlorobenzenesulfenyl chloride (3) 930 mg. { Four . 4 mmol) at room temperature. The mixture was stirred for 30 minutes at room temperature and water (15 ml) was added to the mixture thereof. The toluene phase was separated, washed with water 10 ml twice, and concentrated under reduced pressure. The yellow oil obtained was recrystallized from 10 ml diisopropyl ether, filtered, and dried to yield the objective (8) 800 mg as pale yellow crystal. Performance 82%. 2H-NMR (CDCI3-TMS) d ppm: 1.22 (d, J = 7.2Hz, 6H), 3.64 (sept, 1H), 4.62 (s, 2H), 4.67 (s, 2H), 6.92 (bs, 2H) , 7.07 (bs, 1H), 7.36 (s, 5H), 9.20 (b, 1H).

Example 6 2-Benzyloxymethyl-5- (3,5-dichlorophenylthio) -4- isopropyl-1- (pyridin-4-yl) methyl-lH-imidazole (6) 2-Benzyloxymethyl-4-isopropyl-1- (pyridin-4-yl) -1H-imidazole (5) (10.0 g, 31.1 mmol) was dissolved in toluene (50 ml). The solution was added dropwise to a solution of 3,5-dichlorobenzenesulfenyl chloride (3) (8.0 g, 37.05 mmol) in toluene (24.7 g) under ice cooling for 30 minutes. To the mixture was added dropwise triethylamine (3.5 g, 34.6 mmol) under ice cooling for 1 hour and the mixture was stirred at the same temperature for 1.5 hours. Water (25 ml) was added to the mixture and the toluene phase was separated. The toluene phase was washed with water (25 ml) and each aqueous phase was extracted with toluene (10 ml). The toluene phase was collected, concentrated under reduced pressure to give an oily product, which was crystallized with 50 ml diisopropyl ether, filtered and dried to yield the objective (6) (12.6 g) as a pale yellow crystal. . Performance 81.3%. XH-NMR (CDC13) d ppm: 1.30 (d, J = 7.2 Hz, 6H), 3.08-3.22 (m, 1H), 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, 1H), 7.18-7.36 (m, 5H), 8.38 (d , J = 6.0 Hz, 2H). Reference Example 1 2-Acetyloxymethyl-4-isopropyl-1- (pyridin-4-yl) methyl-1H-imidazole (10a) Compound (5) (20.0 g, 62.2 mmol) was suspended in 35% hydrochloric acid (100 ml). The solution was heated to 85 ° C and stirred for 1 hour. The reaction mixture was cooled to room temperature and water (100 ml) and toluene (44 ml) and toluene (44 ml) were added thereto at room temperature with stirring. The aqueous phase was separated and neutralized with 30% sodium hydroxide, one such ethyl acetate (30 ml) was added with stirring. The obtained slurry was filtered, washed with cold water and dried to yield 2-hydroxy-4-isopropyl-1- (pyridin-4-yl) -iH-imidazole (9) (11.7 g). Performance 81.4%.

^ - R (CDC1) d ppm: 1.16 (d, J = 1.0 Hz, 6H), 2.68-2.89 (m, IH), 4.59 (s, 2H), 5.23 (s, 2H), 6.51 (s, 1H) , 7.03 (d, J = 6.0 Hz, 2H), 8.55 (d, J = 6.0 Hz, 2H).

To a solution of the hydroxide compound obtained above (9) (3.49 g, 15 mmol) and triethylamine (1.83 g, 18 mmol) in dichloromethane (35 ml), was added dropwise acetylchloride (1.32 g, 17 mmol) under a cooling with ice. The water was added to it. The ethane dichloromethane phase was evaporated and the residue was purified by means of column chromatography on silica gel (elution ethyl acetate: methanol = 10: 1) to yield the objective (10a) (3.34 g). Performance 81.1%. XH-NMR (CDC13) d 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, 1H), 6.95 (d, J = 6.0 Hz, 2H), 8.59 (d, J = 6.0 Hz, 2H).

According to the same method described above, the hydroxide compound obtained above (9) (1.16 g, 5 mmol), dichloromethane (12 ml), triethylamine (0.86 g, 8.5 mmol) and benzoylchloride (1.16 g, 8.3 mmol) reacted to produce the objective (10b) (1.65 g). Yield 93.2%. (elution: ethyl acetate) XH-NMR (CDC13) d ppm: 1.34 (d, J = 1.0 Hz, 6H), 2.90-3.10 (m, 1H), 5.29 (s, 2H), 5.45 (s, 2H), 6.74 (s, 1H), 6.99 (d, J = 6.0 Hz, 2H), 7.30-7.90 (m, 5H), 8.55 (d, J = 6.0 Hz, 2H).

According to the same method described above, the hydroxide compound obtained above (9) (1.16 g, 5 mmol), dichloromethane (12 ml), triethylamine (0.76 g, 7.5 mmol) and methyl chloroformate (0.70 g, 7.4 mmol) reacted to yield the objective (10c) (0.40 g), derived from methoxycarbonyl-oxide. Yield 27.6%. XH-NMR (CDC13) d ppm: 1.25 (d, J = 7.0 Hz, 6H), 2.80-3.00 (m, 1H), 3.70, (s, 3H), 5.17 (s, 2H), 5.18 (s, 2H) ), 6.64 (s, 1H), 6.97 (d, J = 6.0 Hz, 2H), 8.59 (d, J = 6.0 Hz, 2H).

Example 7 2- Acetyloxymethyl -5- (3,5-dichlorophenylthio) -4-isopropyl-1- (pyridin-4-yl) methyl-lH-imidazole (11) 10a 11 To a solution of compound (3) (0.97 g, 4.5 mmol) in toluene (1.88 g) was added dropwise to a solution of compound (10a) (0.87 g, 3.2 mmol) in acetonitrile (4 ml) under Cool with ice for 30 minutes. A solution of triethylamine (0.46 g, 4.5 mmol) in acetonitrile (0.5 ml) was added dropwise thereto for 25 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 means of column chromatography on silica gel (elution ethyl acetate) to yield the objective (11) (11.7 g) as a crystal. Performance 82%. P.f. 133-135 ° C. 1 H-NMR (CDCl 3-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 = 6.0 Hz, 2H ).

Reference example 2 2-Hydroxymethyl-5- (3, 5-dichlorofenylthio) -4-isopropyl-1- (pyridin-4-yl) methyl-lH-imidazole (12) To a solution of compound (11) (0.35 g, 0.77 mmol) obtained in Example 7 in ethanol (3.5 ml) was added 1N aqueous sodium hydroxide (0.82 ml) under ice-cooling. 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 (12) (0.31 g). Performance 96.9%.

Reference example 3 2-Carbamoyloxymethyl-4-isopropyl-1- (pyridin-4-yl) .methyl-1H-imidazole (13) 13 The hydroxide compound (9) (15.0 g, 64.9 mmol) was suspended in acetonitrile (150 ml). To the suspension was added dropwise anhydrous hydrochloric acid (5.2 g, 142.5 mmol) in ethyl acetate (42 ml) at room temperature. The mixture was cooled below 0 ° C under a nitrogen atmosphere, and chlorosulfonyl isocyanate (22.0 g, 155.4 mmol) was added dropwise thereto under cooling for 45 minutes. The reaction mixture was stirred at the same temperature for 1 hour, and water (13.5 ml) and 35% hydrochloric acid (13.5 ml) were added thereto. The mixture was stirred at 45 ° C for 1 hour, cooled to room temperature, and neutralized with 20% aqueous sodium carbonate. The mixture was kept stationary and separated. The organic phase was washed with water, and the aqueous phase was extracted with ethyl acetate. To the residue was added diisopropyl ether (80 ml), and the solution was stirred for 1 hour at room temperature. The obtained slurry was filtered, washed with diisopropyl ether and dried to yield the objective (13) (14.8 g). Yield 83.2%. XH-NMR (CDCI3-TMS) d ppm: 1.25 (d, J = 7.0 Hz, 6H), 2.80-3.00 (m, 1H), 4.95 (bs, 2H), 5.10 (s, 2H), 5.20 (s, 2H), 6.63 (s, 1H), 6.97 (d, J = 5.2 Hz, 2H), 8.57 (d, J = 5 .0 Hz, 2H).

Example 8 2-Carbamoyloxymethyl-5- (3,5-dichlorophenylthio) -4-isopropyl-1- (pyridin-4-yl) methyl-lH-imidazole (14) The compound (13) (250 mg, 0.91 mmol) was dissolved in N, N-dimethylformamide (4 ml). The solution was cooled to below -30 ° C under a nitrogen atmosphere. To the solution was added, alternately every four minutes, a solution of compound (3) (77 mg, 0.36 mmol) in toluene (150 mg) and a solution of triethylamine (36 mg)., 0.36 mg) in toluene (150 mg), and additionally a solution of compound (3) (77 mg, 0.36 mmol) in toluene (150 mg) was added. The reaction mixture was stirred at -30 ° C for 30 minutes, and the ethyl acetate and sodium aqueous hydrogen carbonate was added thereto. The objective (14) was extracted in the ethyl acetate phase. The dilute aqueous hydrochloric acid was added to the ethyl acetate phase to transfer the objective compound into the aqueous phase. The aqueous solution was neutralized by means of sodium aqueous hydrogen carbonate and extracted with ethyl acetate. The extract was dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give an oily residue.

The oily residue was dissolved in methanol (0.9 1), and water (0.7 ml) was added dropwise thereto for 1-2 minutes at room temperature for crystallization. The suspension was stirred for 30 minutes at t.a. additionally for 30 minutes under ice cooling, filtered, washed with 50% aqueous methanol, and dried to yield the objective (14 = (250 mg) as a white crystal, yield 61%, mp 88 ° C ( dec) XH-NMR (CDC13-TMS) d ppm: 1.32 (d, J = 6.9Hz, 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, 1H), 8.46 (b, 2H). Elemental analysis (C20H20C12N 02S 0.5 H20) Caled. (%): 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 2HC1 salt of the compound (14): mp 214 - 222 ° C (dec) Reference example 4 2, 2-Dichloro-3-methylbutylaldehyde (16) 16 To a mixture of isovalelaldehyde (15) (192 g, 2.23 mmol) and N, -dimethylformamide (230 ml) was introduced chlorO (316 g, 4.46 mol) at below 60 ° C. The mixture was cooled, mixed with water (385 ml) and separated. The organic phase was washed with sodium aqueous hydrogen carbonate (350 g), and each aqueous phase was extracted with toluene (115 ml). The organic phase was collected to yield a solution of objective (16) in toluene (440 g). Performance 75%. xH-NMR (CDCl3-TMS) d ppm: 1.15 (d, J = 6.6Hz, 6H), 2.56 (sept, J = 6.6Hz, 1H), 9.24 (s, 1H). 1, -Dibenzyloxy-2-butene (18) To 48% aqueous sodium hydroxide (127.8 g) was added tetra-n-butylammonium bromide (3.3 g, 10 mmol). The mixture was heated to 60 ° C. To the mixture was added 2-buten-1,4-diol (17) (30.0 mmol), to which was added dropwise benzyl chloride (94.8g, 743 mmol) at 80 * ± 15 ° C. The mixture was stirred at the same temperature for 2 hours. The reaction mixture was cooled, and separated after the addition of water (90 m). Sulfuric acidic brine was added to the organic phase. The solution was neutralized by means of "aqueous sodium hydrogen carbonate," separated, mixed with ethyl acetate and concentrated under reduced pressure to yield objective (18) (104.5 g, quant.) As an oil residue. . XH-NMR (CDCI3-TMS) d ppm: 4.05 (d, - 3.8 Hz, 2H), 4. 48 (s, 2H), 5.78 (, 2H), 7.31 (m, 10H).

Benzyloxyethoaldehyde (19) 18 19 1, 4-Dibenzyloxy-2-butene (18) (104.5 g, 340 mmol) obtained above was dissolved in methanol (1458 ml). The solution was cooled to below -60 ° C under a nitrogen atmosphere. The ozone was introduced thereto at about -60 ° C until the starting material disappeared, and then the excess amount of the ozone gas was removed by pumping nitrogen gas. To the solution was added dropwise a solution of triphenylphosphine (107.2 g, 409 mmol) in ethyl acetate (550 mL) at -60 ° C to reduce the reaction intermediate. The reaction mixture was warmed to room temperature, and concentrated under reduced pressure to yield an oily mixture of the phosphorus compound and objective (19) (321.6 g, quantitative). 2-Benzyloxymethyl-4-isopropyl-1H-imidazole (7) The oil residue of benzyloxy acetaldehyde (19) (268 g, approximately 0.57 mol) obtained in the previous (II) and the extract of 2,2-dichloro-3-methylbutylaldehyde (16) (183 g, approximately 0.70 mol) obtained in the former (I) were mixed with acetonitrile (276 ml). 25% aqueous ammonium (692 g, 10.2 mol) was added thereto. The mixture was stirred at 45 ° C for 8 hours, extracted with toluene 213 ml and separated to yield the objective extract (7) (725 g). Yield 70%. The compound (7) can be isolated as a crystal from the n-hexane. XH-NMR (CDCI3-TMS) d ppm: 1.23 (d, J = 6.8 Hz, 6H), 2.88 (sept, J = 6.8 Hz, 1H), 4.51 (s, 2H), 4.58 (s, 2H), 6.65 (d, J = 1.0 Hz, 1H), 7.1-7.4 (m, 5H). 4-chloromethylpyridine hydrochloride (21) 21 4-Hydroxymethylpyridine (20) (54.4 g, 0.50 mol) was dissolved in acetonitrile 2020 ml. The solution was added dropwise to a mixture of thionyl chloride (65.3 g, 0.55 mol) and acetonitrile (109 ml) below 50 ° C. The mixture was stirred at the same temperature for 1 hour, then at room temperature to produce a slurry (quantitative) of the object (21). XH-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). 2. 2-Benzyloxymethyl-4-isopropyl-1- (pyridin-4-yl) methyl-1H-imidazole nitrate (22) " The extract of 2-benzyloxymethyl-4-isopropyl-1H-imidazole (7) (725 g, approximately 0.40 mol) obtained in the above (III) was neutralized by means of aqueous sulfuric acid, mixed with the hydrochloride 4-chloromethylpyridine (21) (approximately 0.50 mol) obtained in the former (IV) and water, and then made alkaline by means of sodium hydroxide. The mixture separated. The aqueous phase was extracted with toluene (65 ml), and the organic phase was collected.

The organic phase was concentrated to about 850 ml, mixed with sodium hydroxide (62.6 g), and stirred at about 40 ° C for 5 hours. The reaction mixture was mixed with water (226 ml) and separated. The aqueous phase was extracted with toluene (65 ml), and the organic phase was collected.

The organic phase was mixed with 20% aqueous sulfuric acid (348 g) and the aqueous phase containing the objective compound was separated. The organic phase was extracted with water (65 ml), and the aqueous phase was collected. The aqueous phase was mixed with 20% aqueous sodium hydroxide water (282 g) and extracted with ethyl acetate (130 ml). The organic phase was washed with brine, and each aqueous phase was extracted with ethyl acetate (65 ml). The organic phase was collected, concentrated without moisture under reduced pressure. The residue was mixed with ethyl acetate (523 ml) and methanol (131 ml), crystallized by means of concentrated sulfuric acid (82.9 g, 0.89 mol), filtered, and dried to yield the objective (22) (161.3). g) like a pale yellow crystal. Performance 90%. P.f. 155 ° C (dec) The free compound of the objective (22) can be isolated as a crystal by means of the diisopropyl ether. XH-NMR (CD3OD-TMS) d 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), 7.4Í (d, J = 1.0 Hz, 1H), 7.74 (d, J = 6.8 Hz, 2H), 8.67 (d, J = 6.8 Hz, 2H). 2-Benzyloxymethyl-5 (3,5-dichlorophenylthio) -4-isopropyl-1- (pyridin-4-yl) methyl-lH-imidazole (6) 2. 2-Benzyloxymethyl-4-isopropyl-1- (pyridin-4-yl) -lH-imidazole nitrate. (22) (13.9 g, 31 mmol) was suspended in toluene (50 ml) and water (12 ml). The suspension was neutralized by means of 30% aqueous sodium hydroxide. The toluene phase was washed with water (40 ml) and concentrated without moisture. The residue was dissolved in toluene (50 ml). The solution was added dropwise to a solution of 3,5-dichlorobenzenesulfenylchloride (3) (7.9 g, 37 mmol) in toluene (24.7 g) under cooling with ice. To the mixture was added dropwise triethylamine (3.5 g, 34 mmol) under ice cooling for 1 hour. The mixture was stirred at the same temperature for 2.5 hours and mixed with water (25 ml). The toluene phase was separated and washed with water (25 ml), and the aqueous phase was re-extracted with toluene (10 ml). The toluene phase was collected and concentrated under reduced pressure. The oily residue was crystallized by slowly adding diisopropyl ether (50 ml), filtered, and dried to yield the objective (6) (13.0 g) as a pale yellow crystal. Performance 84%.

XH-NMR (CDCl 3) d ppm: 1.30 (d, J = 1.2 Hz, 6H), 3.08- 3.22 (m, 1H), 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, IH), 7.18 - 7.36 (m, 5H), 8.38 (d, J = 6.0 Hz, 2H). 2-Hydroxymethyl-5- (3,5-dichlorophenylthio) -4-isopropyl-1- (pyridin-4-yl) methyl-lH-imidazole (12) To the compound (6) was added concentrated hydrochloric acid (50 ml). The mixture was heated to 90 ° C for 2 hours and then cooled. Water (50 ml) and toluene (20 ml) were added to the mixture. The aqueous phase was separated and neutralized by means of 30% sodium hydroxide. The compound (12) was extracted with ethyl acetate (50 ml), and the ethyl acetate phase was washed with water (30 ml). Each aqueous phase was extracted with ethyl acetate (20 ml). The ethyl acetate phase was collected and concentrated under reduced pressure to yield an oily residue. To the oily residue was slowly added diisopropyl ether (50 ml) for crystallization. The obtained slurry was stirred at room temperature for 30 minutes, filtered, washed with diisopropyl ether (30 ml) and dried to yield the compound (12) (10.4 g) as a white crystal. Yield from compound (22): 82%. 2-Carbamoyloxymethyl-5- (3,5-dichlorophenylthio) -4-isopropyl-1- (pyridin-4-yl) methyl-lH-imidazole (14) The hydroxide compound (12) (2.00 g, 4.9 mmol) was suspended in ethyl acetate (20 ml). The solution was cooled to -30 ° C under a nitrogen atmosphere. ] To the solution was added dropwise chlorosulfonyl isocyanate (1.66 g, 11.4 mmol) under a nitrogen atmosphere at -30 ° C for 30 minutes, and the mixture was stirred at the same temperature for 1 hour. To the mixture was added dropwise water (2 ml), and the mixture was heated to 0 ° C. To the mixture was added 35% hydrochloric acid (2 ml) and methanol (4 ml), and the solution was stirred at 40 ° C for 1 hour. The mixture was cooled to room temperature and neutralized by means of 20% aqueous sodium carbonate. The organic phase was separated, washed with water, concentrated, and dried. To the residue was added methanol (6 ml) for the solution, then water (6 ml) at room temperature for the temperature. The obtained slurry was filtered, washed with 50% aqueous methanol (6 ml) and dried to yield compound (14) (2.06 g). Yield 93.2%. 2H-NMR (CDC13-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, IH), 8.46 (b, 2H). Elemental analysis (C20H20C12N 02S * 0.5H20) Caled. 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 2HC1 salt the compound (14): p.f. 214 - 222 ° C (dec) INDUSTRIAL APPLICABILITY The present invention provides the process for producing arylsulfenyl halide and a precursor thereof, alkyl aryl sulfide, which is useful as a starting material for a pharmaceutical composition, especially an antiviral composition or a composition for the treatment of AIDS. The present process is easy to manage, economical, and applicable to a large-scale 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 description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (19)

CLAIMS 1. A process for producing a compound of formula (II): where -that Hal1 represents halogen and
1. R1 and R2 each independently represent halogen, alkyl, alkoxide, nitro or cyano; characterized in that it comprises allowing a halogenating agent to react with a compound of the formula (I) where Alk represents the branched alkyl and R1 and R2 are as defined above.
2. 2. A process for producing a compound of formula (IV): (IV) wherein R1 and R2 are as defined above, R3 represents hydrogen or an organo residue, R4 represents an organic residue and R5 represents hydrogen or an organic residue, characterized in that it comprises preparing a compound of the formula (II): where Hal1 represents the halogen and R1 and R2 are as defined above, by the process according to claim 1, after reacting the compound of the formula (II) with a compound of the formula (III): where R3, R4 and R are as defined above.
3. 3. A process for producing a compound of formula (I): wherein Alk, R 1 and R 2 are as defined above, characterized in that it comprises reacting a compound of formula (V): Alk-SH (V) where Alk is as defined above, with a compound of the formula (VI): where Hal2 represents the halogen and R1 and R2 are as defined above, in the presence of a base.
4. 4. A process for producing a compound of formula (II): (") Wherein Hal1, R1 and R2 are as defined above, characterized in that it comprises preparing a compound of the formula (I): wherein Alk, R1 and R2 are as defined above, by the process according to claim 3, after allowing a halogenating agent to react with the compound of the formula (I).
5. 5. A process for producing a compound of formula (IV): wherein R1C R2 / - R3 / - R4 and R5 are as defined above, by the process according to claim 4, characterized in that the compound of the formula (II) is then reacted with a compound of the formula (III) ): where R3, R4 R5 are as defined above.
6. 6. The process according to claim 1 or 4 characterized in that the halogenating agent is chlorine.
7. 7. The process according to claim 3, characterized in that it was carried out in the presence of a phase transfer catalyst.
8. 8. The process according to claim 7, characterized in that the phase transfer catalyst is a quaternary ammonium salt or a quaternary phosphonium salt.
9. 9. The process according to claim 1 or 3 characterized in that Alk is isopropyl or tert-butyl.
10. 10. The process according to any of claims 1-5 characterized in that R1 and R2 each independently represents the halogen.
11. 11. The process according to claim 2 or 5 characterized in that R3 represents hydrogen or optionally substituted heteroarylalkyl, R4 represents -AX- where A represents -CH2OCH2 or -CH20-, X represents optionally substituted aryl or -COB where B represents optionally substituted alkyl , optionally substituted alkoxide, optionally substituted aryl or optionally substituted amino and R5 represents optionally substituted alkyl.
12. 12. The process according to claim 11, characterized in that RJ represents optionally substituted pyridylmethyl.
13. 13 A compound of the formula '(la): characterized in that R11 and R21 each independently represent halogen, alkyl, nitro or cyano and Alk is as defined above, with the proviso that (l) R11 and R21 represents nitro and Alk represents isopropyl, (2) Rn, R21 and Alk represents tert-butyl, (3) R > n1 R¿ represents chlorine and Alk represents iso-propyl, and (4) R11 and R21 represent fluorine and Alk represents tert-butyl are excluded.
14. The compound according to claim 13 characterized in that R11 and R21 each independently represents the halogen.
15. 15. A process for producing a compound of formula (I): where Alk, R, 1 and ,. R2 are as defined above, the supplied (l) R11 and R21 represents the nitro and Alk represents the. isopropyl, (2) R11, R21 and Alk represent tert-butyl, (3) R11 and R21 represents chlorine and Alk represents iso-propyl, and (4) R11 and R21 represent fluorine and Alk represents tert-butyl are excluded, characterized in that they comprise reacting a compound of the formula (V): A1K-SH (V) wherein Alk is presented as defined above, with a compound of the formula (VI): where Hal2 represents halogen and 1 and R2 are like ^ = "~ were previously defined, in the presence of a base.
16. 16. The process according to claim 15, characterized in that it was carried out in the presence of a phase transfer catalyst.
17. 17. The process according to claim 16, characterized in that the catalyst is a quaternary ammonium salt or a quaternary phosphonium salt.
18. 18. The process according to any of claim 15 or 15 characterized in that Alk is isopropyl or tert-butyl.
19. 19. The process according to any of claims 1, 2, 4, 5 or 15 characterized in that R1 and R2 each independently represent the halogen.