MXPA97009130A

MXPA97009130A - Process for the synthesis of acid derivatives vinilsulfen

Info

Publication number: MXPA97009130A
Application number: MXPA/A/1997/009130A
Authority: MX
Inventors: Warren Hoard David; Douglas Luke Wayne
Original assignee: Eli Lilly And Company; Hoard David W; Luke Wayne D
Priority date: 1995-06-07
Filing date: 1997-11-26
Publication date: 1998-10-15

Abstract

The present invention relates to new derivatives of vinyl sulfonic acid and to a new process for its synthesis. These compounds are useful for the synthesis of benzo [b] thiophenes, in particular 2-aryl-benzo [b] thiophene

Description

PROCESS FOR THE SYNTHESIS OF DERIVATIVES OF THE VINYL SOLOPHENIC ACID DESCRIPTION OF THE INVENTION The present invention relates to new vinylsulfenic acid derivatives and to a new process for their synthesis. These compounds are useful for the synthesis of benzo [b] thiophenes, in particular 2-aryl-benzo [b] thiophenes. Benzo [b] thiophenes have been prepared by a number of different synthetic routes. One of the most widely used methods is the oxidative cyclization of o-mercaptocinamic acids. This route is limited to the preparation of benzo [b] thiophene-2-carboxylates. The 2-phenylbenzo [b] thiophenes are prepared by an acid-catalyzed cyclization of 2-phenylthioacetaldehyde dialkyl acetals. The unsubstituted benzo [b] thiophenes are prepared by catalytic condensation of styrene and sulfur. The 3-substituted benzo [b] thiophenes are prepared by acid-catalyzed cyclization of arylthiomethyl ketones; however, this route is limited to the preparation of 3-alkylbenzo [b] thiophenes. See Campaigne, "Thiophenes and their Benzo Derivatives: (iii) Synthesis and Applications", in Comprehensive Heterocyclic Chemistry (Katritz and Rees, eds.), Volume IV, Part III, 863-934 REF: 26085 (1984). 3-Chloro-2-phenylbenzo [b] thiophene is prepared by the reaction of diphenylacetylene with sulfur dichloride. Barton and Zikra, J. Org. Chem. , 35, 1729-1733 (1970). Benzo [b] thiophenes have also been prepared by pyrolysis of styryl sulphoxides. However, the low yields and the extremely high temperatures that are used make this route not suitable for production scale synthesis. See Ando, J. Chem. Soc, Chem. Comm., 704-705 (1975). Sulfenic acids have been postulated as key intermediates in a variety of chemical reactions; however, there are very few examples of isolation of these compounds. See Shelton and Davis, J. Am. Chem. Soc., 89 (3), 718-719 (1968) and Davis et al. , J. Am. Chem. Soc., 100, 2844 (1978). Sulfenic acids have been generated in situ and cyclized intramolecularly or intermolecularly with olefins and acetylenes. See Mazzanti et al. , J. Chem. Soc., Perkin Trans. I, 3299-3004 (1944) and Davis et al. , J. Org. Chem. , 45, 1650-1653 (1980). A series of trimethylsilylarene sulfonates has been prepared from the corresponding N-benzylidenarenosulfinamides; however, the yield of the trimethylsilyl ester was generally very low. Davis et al. , J. Org. Chem. , 45, 1650-1653 (1980).

The preparation of 6-hydroxy-2- (4-hydroxyphenyl) benzo- [b] thiophenes has been described in U.S. Patent Nos. 4,133,814 and 4,380,635. A process described in these patents is the intramolecular cyclization catalyzed by acid / rearrangement of a - (3-methoxyphenylthio) -4-methoxyacetophenone. Reaction of this raw material in a pure polyphosphoric acid at a temperature of about 85 to about 90 ° C, produces a mixture of about 3: 1 of two regioiso steric products: 6-methoxy-2- (4-methoxyphenyl) -benzo [b] thiophene and 4-methoxy-2- (4-methoxyphenyl) -benzo [b] thiophene. These isomeric benzo [b] thiophenes coprecipitate in the reaction mixture, producing a mixture containing both compounds. To obtain a single regioisomer, the regioisomers must be separated, for example by chromatography or by fractional crystallization. However, there is currently a need for an efficient and regiospecific synthesis of 2-arylbenzo [b] thiophenes from easily obtainable raw materials. The present invention relates to new vinylsulfenic acid derivatives: new sulfenate silanesters, sulfenamides and disulfides, and to a process for the synthesis of vinylsulfenic acid derivatives. Specifically, the present invention relates to a compound of the Formula III wherein: R 1 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo or amino; R2 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo or amino; R4 is a radical OSi (R) 3, NR5R6 or SRe; each R is independently an alkyl, aryl, or arylalkyl radical of 1 to 6 carbon atoms; R5 and Re are independently a hydrogen atom, an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms, or R5 and Re together with the nitrogen atom form a ring which is selected from the group consisting of piperidine, pyrrolidine, morpholine or hexa ethylimine; and R8 is an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms. Thus, the present invention individually includes the E and Z isomers, or mixtures thereof, of the compounds of Formula III. These regioisomers E and Z are represented by the following structures: Another aspect of the present invention is a process for the preparation of silyl esters of sulfenate, sulfenamides and disulfides. The present invention relates to a process for the preparation of a compound of the Formula III wherein: R 1 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo or amino; R2 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo or amino; R4 is a radical OSi (R) 3, NR5R6 or SRs; each R is independently an alkyl, aryl, or arylalkyl radical of 1 to 6 carbon atoms; R5 and R1 are independently a hydrogen atom, an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms; or R5 and Re together with the nitrogen atom form a ring that is selected from the group consisting of piperidine, pyrrolidine, morpholine or hexamethylimine; and Rs is an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms; which comprises: (1) reacting a compound of the Formula O II wherein: R1 and R2 are as defined above, and R3 is an alkyl radical of 2 to 10 carbon atoms, heat-labile or unstable to the acid, alkenyl of 4 to 10 carbon atoms, or aryl (alkyl of 1 to 10 carbon atoms). carbon); with a silylating reagent to produce a sulfenate silyl ester of the Formula where: Ri and R2 are as previously defined; R7 is a radical 0 Si (R) 3; and each R is independently an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms: (2) optionally, reacting the silynester of sulfenate with an amine of the Formula HNR5R6, wherein R5 and Re are as previously defined; or (3) optionally reacting the sulfenate silanester with a mercaptan of the Formula HSR8, wherein RQ is as previously defined, in the presence of an amine base. One aspect of the present invention is a process for the synthesis of sulfenate silylesters of Formula IV. In particular, the present invention relates to a process for preparing a compound of the Formula wherein: R 1 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo or amino; R2 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo or amino; R7 is a radical OSi (R) 3, - and each R is independently an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms; which comprises reacting a compound of the Formula wherein: R1 and R2 are as previously defined, and R3 is an alkyl radical of 2 to 10 carbon atoms, thermolabile or unstable to the acid, alkenyl of 4 to 10 carbon atoms or aryl (alkyl of 1 to 10 carbon atoms) ); with a silylation reagent. Another aspect of the present invention is a process for the synthesis of sulfenamides of Formula V. In particular, the present invention relates to a process for the preparation of a compound of the Formula wherein: R 1 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo, amino; R2 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo, amino; and R5 and Rβ are independently a hydrogen atom, an alkyl, arylalkyl or aryl radical of 1 to 6 carbon atoms; or R5 and Re together with the nitrogen atom form a ring that is selected from the group consisting of piperidine, pyrrolidine, morpholine or hexamethylimine; comprising the steps of: (1) reacting a compound of the Formula wherein: R1 and R2 are as defined above, and R3 is an alkyl radical of 2 to 10 carbon atoms, heat-labile or unstable to the acid, alkenyl of 4 to 10 carbon atoms, or aryl (alkyl of 1 to 10 carbon atoms). carbon); with a silylating reagent to produce a sulfenate silyl ester of the Formula where: Rl and R2 are as previously defined; R7 is a radical OSi (R) 3, - and each R is independently an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms; and (2) reacting the silynester of sulfenate with an amine of the formula HNR5R6, wherein R5 and Re are as previously defined.

Another aspect of the present invention is a process for the synthesis of disulfides of Formula XIV. In particular, the present invention relates to a process for preparing a compound of the Formula wherein: R 1 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo, amino; R2 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo, amino; and R? is an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms; comprising the steps of: (1) reacting a compound of the Formula wherein: R1 and R2 are as previously defined, and R3 is an alkyl radical of 2 to 10 carbon atoms, thermolabile or unstable to the acid, alkenyl of 4 to 10 carbon atoms or aryl (alkyl of 1 to 10 carbon atoms) ); with a silylating reagent, to produce a sulfenate silyl ester of the Formula where: Rl and R2 are as previously defined; R7 is a radical OSi (R) 3, - and each R is independently an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms; and (2) reacting the sulfenate silyl ester with a mercaptan of the Formula HSRβ, wherein Rβ is as previously defined, in the presence of an amine base. Another aspect of the present invention is a process for the synthesis of a compound of the Formula wherein: R9 is a hydrogen atom, a halo, amino or hydroxyl radical; Rio is a hydrogen atom, a halo, amino or hydroxyl radical; Rn and R12 are independently an alkyl radical of 1 to 4 carbon atoms, or Rn and R12 together with the adjacent nitrogen atom form a heterocyclic ring which is selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino and morpholino; and HX is HCl or HBr; comprising the steps of: (a) performing the cyclization, in the presence of an acid catalyst, of a compound of the Formula III wherein: R 1 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo or amino; R2 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo or amino; Y R4 is a radical OSi (R) 3, NR5R6 or SRβ; each R is independently an alkyl, aryl, or arylalkyl radical of 1 to 6 carbon atoms; R5 and Re are independently a hydrogen atom, an alkyl radical, or aryl of 1 to 6 carbon atoms; or R5 and Re together with the nitrogen atom form a ring that is selected from the group consisting of piperidine, pyrrolidine, morpholine or hexamethylimine; Rβ is an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms; to prepare a benzothiophene compound of the Formula where Ri and R2 are as previously defined; (b) acylating the benzothiophene compound with an acylating agent of the Formula XII where: Rii »R12 and HX are as previously defined; and R13 is a chloro, bromo or hydroxyl radical; in the presence of BX'3, wherein X 'is chlorine or bromine; (c) when Ri and / or R2 is an alkoxy or arylalkoxy radical of 1 to 4 carbon atoms, one or more phenolic groups of the acylation product of step (b) are dealkylated by further reaction with BX'3, where X 'is as previously defined; and (d) isolating the compound of Formula XIII. The term "acid catalyst" represents a Lewis acid or a Bronsted acid. The acids of Representative Lewis are zinc chloride, zinc iodide, aluminum chloride and aluminum bromide. Representative Brónsted acids include: inorganic acids such as sulfuric acid and phosphoric acid, carboxylic acids such as acetic acid and trifluoroacetic acid; sulphonic acids such as methanesulfonic acid, benzenesulfonic acid, 1-naphthalenesulfonic acid, butanesulfonic acid, ethanesulfonic acid, 4-ethylbenzenesulfonic acid, 1-hexanesulfonic acid, 1,5-naphthalenedisulfonic acid, 1-octanesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic; and polymeric arylsulfonic acids such as Nafion, Amberlyst® or Amberlite®. Preferred acids for use in the catalytic processes of the present invention are sulphonic acid or polymeric sulfonic acids. More preferably, the acid catalysts are sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid and p-toluenesulfonic acid. The most preferred acid catalyst is p-toluenesulfonic acid. In the above Formula, the term "C 1 -C 4 alkoxy" represents radicals such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and the like. The term "halo" refers to fluoro, chloro, bromo or iodo radicals. The term "alkyl of 1 to 6 carbon atoms" represents a straight or branched alkyl chain, having 1 to 6 carbon atoms. Typical alkyl radicals of 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, 2- methylpentyl and the like. The term "C 1 -C 4 alkyl" represents a straight or branched alkyl chain having from 1 to 4 carbon atoms and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, i groups. -butyl and t-butyl.

The term "aryl" represents groups such as phenyl and substituted phenyl. The term "substituted phenyl" represents a phenyl radical substituted with one or more portions which are selected from the group consisting of halo, hydroxy, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, trichloromethyl and trifluoromethyl. Examples of a substituted phenyl group include 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3- chloro-4-fluorophenyl, 2-fluorophenyl, 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-propylphenyl, 4-n-butylphenyl, 4-t-butylphenyl, 3-fluoro-2-methylphenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 2,6-dimethylphenyl, 2-fluoro-5-methylphenyl, 2,4,6-trifluorophenyl, 2-trifluorophenylmethyl, 2-chloro-5-trifluoromethylphenyl, 3,5-bis- (trifluoromethyl) phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3,5-dimethoxyphenyl, 4-hydroxy-3-methylphenyl, 3,5-dimethyl-4-hydroxyphenyl, 2-methyl-4-nitrophenyl, 4-methoxy-2-nitrophenyl and the like. The term "aralkyl" represents an alkyl radical of 1 to 4 carbon atoms carrying one or more aryl groups. Representative of this group include the benzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl radicals (such as p-chlorobenzyl, p-bromobenzyl, p-iodobenzyl), 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4- phenylbutyl, 2-methyl-2-phenylpropyl, (2,6-dichlorophenyl) -methyl, bis (2,6-dichlorophenyl) methyl, (4-hydroxyphenyl) -methyl, (2,4-dinitrophenyl) methyl, diphenylmethyl, triphenylmethyl. , (p-methoxyphenyl) -diphenylmethyl, bis (p-methoxyphenyl) methyl, bis (2-nitrophenyl) methyl and the like. The term "arylalkoxy" represents an alkoxy radical of 1 to 4 carbon atoms carrying one or more aryl groups. Representative of this group include benzyloxy radicals, o-nitrobenzyloxy, p-nitrobenzyloxy, p-halobenzyloxy (such as p-chlorobenzyloxy, p-bromobenzyloxy, p-iodobenzyloxy), 1-phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy , 2-methyl-2-phenylpropoxy, (2,6-dichlorophenyl) methoxy, bis (2,6-dichlorophenyl) methoxy, (4-hydroxyphenyl) methoxy, (2,4-dinitrophenyl) methoxy, diphenylmethoxy, triphenylmethoxy, (p-methoxyphenyl) -diphenylmethoxy, bis (p-methoxyphenyl) methoxy, bis (2-nitrophenyl) methoxy, and the like. The term "alkyl of 2 to 10 carbon atoms thermolabile or unstable to the acid, alkenyl of 4 to 10 carbon atoms or aryl (alkyl of 1 to 10 carbon atoms)" represents a radical that is easily removed from the sulfoxide group (SO) ) by heating or by a treatment with the acid catalyst. The alkyl radicals of 2 to 10 carbon atoms which are heat-labile or acid-stable are straight or branched alkyl chains having 2 to 10 carbon atoms and having at least one beta-hydrogen atom. Representative heat-stable or acid-stable alkyl radicals of 2 to 10 carbon atoms include ethyl, n-propyl, i-propyl, 1,1-dimethylpropyl, n-butyl, sec-butyl, t-butyl, 1, 1- radicals. dimethylbutyl, 2-methylbutyl, 3-methylbutyl, 1-methylbutyl, 1, 2-dimethylbutyl, 1,3-dimethylbutyl, 2,4-dimethylbutyl, 3, 3-dimethylbutyl, n-pentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-hexyl and the like. The alkenyl groups of 4 to 10 carbon atoms which are heat-labile or acid-stable are straight or branched alkenyl chains having from 4 to 10 carbon atoms, at least one unsaturation site and either a beta-hydrogen or delta atom -hydrogen. Representative alkylaryl radicals of 4 to 10 carbon atoms or representative acid-stable radicals include 2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 2-methyl-3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3- pentenyl, 4-methyl-3-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like. The term "heat-labile or acid-stable aryl (C1-C10 alkyl)" represents alkyl groups of 2 to 10 carbon atoms that are heat-labile or acid-labile, additionally containing one or more aryl groups and aryl-substituted methyl groups. Representative aryl (C 1 -C 10) alkyl radicals include benzyl, diphenylmethyl, triphenylmethyl, p-methoxybenzyl, 2-phenylethyl, 2-phenylpropyl, 3-phenylpropyl radicals and the like. A group of products of the present invention are the sulfenate silylesters. In particular, the compounds of Formula III wherein R 4 is 0 Si (R) 3 and each R is independently an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms and the compounds of Formula IV are silyl esters of sulfenic acids. Preferred sulfenate silylesters are abbreviated using the nomenclature known in the field of chemistry, as shown in the following Table TABLE 1 Abbreviation Silyl Group TMS trimethylsilyl TES triethylsilyl TIPS triisopropylsilyl DMIPS dimethylisopropylsilyl DEIPS diethylisopropylsilyl TDS dimethylhexysilyl TBDMS t-butyldimethylsilyl TBDPS t-butyldiphenylsilyl TBS tribenzylsilyl TPS triphenylsilyl DPMS diphenylmethylsilyl TBMPS t-butyldy (methoxyphenyl) silyl The term "silylating reagent" represents a compound or combination of compounds used to transform the intermediate sulfenic acid into a sulfenate silylester. Representative silylating reagents include bis (trialkylsilyl) ureas, such as 1,3-bis (trimethylsilyl) urea, 1,3-bis (triethylsilyl) urea, 1,3-bis (dimethylisopropylsilyl) urea, 1,3-bis ( triisopropylsilyl) urea, 1,3-bis (diethylisopropylsilyl) urea, 1,3-bis (dimethylhexylsilyl) urea, and 1,3-bis (t-butyldimethylsilyl) urea, bis (trialkylsilyl) ureas, such as 1,3-bis (triphenylsilyl) urea; bis (diarylalkysilyl) ureas, such as 1,3-bis (diphenylmethylsilyl) urea and 1,3-bis (t-butyldiphenylsilyl) urea; and hexaalkyldisilyl canenes, such as hexamethyldisilylzan; or combinations of a hexaalkyldisilylzanne and a catalytic amount of a chlorotrialkylsilane, such as chlorotrimethylsilane.

The compounds of Formula III exist in two regioisomeric forms, the E and Z forms. These regioisomers E and Z are represented by the following structures: The raw material compounds for the processes of the present invention can be prepared by a number of routes. A method for the preparation of compounds of Formula II is shown in Scheme I. Scheme 1 In general, a compound of Formula VII is converted to a styrylsulphide by reaction with a mercaptan of Formula HSR3 in the presence of a Lewis acid. The compound of Formula VIII, subsequently, is oxidized to obtain a styrylsulfoxide, which is a compound of Formula II. More specifically, a compound of the Formula VII wherein Ri and R2 are as defined above, treated with a Lewis acid such as titanium (IV) chloride. This reaction is carried out in an anhydrous organic solvent, such as anhydrous tetrahydrofuran, at a temperature of about 0 to about 35 ° C. After about 15 minutes to about one hour, the reaction mixture is treated with an amine base and a mercaptan of the Formula HSR3, wherein R3 is an alkyl radical of 1 to 10 carbon atoms, thermolabile or unstable to the acid, alkenyl of 4 to 10 carbon atoms or aryl (alkyl of 1 to 10 carbon atoms). Preferably, the mercaptan and the amine base are added in the form of a solution in the reaction solvent. A representative amine base is triethylamine. After the addition of the mercaptan and the amine base, the reaction mixture is generally heated to a temperature of about 35 to about 65 ° C, preferably to about 50 ° C. The products of this reaction can be purified using techniques known in the field of chemistry, such as crystallization or chromatography. Then, the compound of Formula VIII wherein Ri, R2 and R3 are as defined above, is oxidized to produce the compounds of Formula II. Oxidizing agents suitable for this reaction are peracids, such as peracetic acid and m-chloroperoxybenzoic acid, in addition to hydrogen peroxide. This oxidation reaction is typically carried out in an organic solvent, such as toluene, methylene chloride, chloroform or carbon tetrachloride. When a peracid is used as an oxidant, the reaction is generally carried out at a temperature of about -30 to about 15 ° C, preferably at about -20 ° C. The products of the reaction are easily purified by recrystallization.

When R3 is t-butyl, the crystalline product of this reaction sequence is regioisomer E of Formula II. When R3 has a tertiary carbon adjacent to the sulfur atom, the Z-regioisomers of compounds of Formula II can be selectively prepared via a second route as shown in Scheme 2.

Scheme 2 Generally a benzyl alcohol, which is a compound of Formula IX, is reacted with a mercaptan of Formula R3SH to produce a benzylsulfide, which is a compound of Formula X. This benzyl sulfide is reacted with a strong base, forming a benzylic anion which is condensed with a benzaldehyde. This condensation product is reacted with an acid chloride and the resulting intermediate is treated with a strong second base, to produce a styrylsulfide, which is a compound of Formula VIIIZ. This styrylsulfide is subsequently oxidized with an oxidizing agent to produce the compound of Formula IIZ.

- - The first step in the synthesis of the styrylsulfoxide Z compounds is the conversion of a benzyl alcohol to a benzyl sulfide, which is a compound of the Formula X. The reaction of the compound of the Formula IX wherein R2 is as defined above, with a mercaptan of the formula R3SH wherein R3 is an alkyl radical of 2 to 10 carbon atoms thermolabile or unstable to the acid, alkenyl of 4 to 10 carbon atoms or aryl (alkyl of 1 to 10 carbon atoms) having an tertiary carbon adjacent to the sulfur atom, in the presence of a Lewis acid, produces the benzylsulfide of Formula X. The Lewis acids suitable for this transformation are zinc bromide, zinc chloride, zinc iodide, ferric chloride, chloride of titanium (IV), aluminum trichloride and aluminum tribromide, preferably zinc chloride. The reaction is generally carried out in an organic solvent such as 1,2-dichloroethane or methylene chloride. When the reaction is carried out at room temperature, it concludes after about 18 hours. The benzylsulfide is reacted with a strong base to form a benzylic anion. Suitable strong bases for this reaction include metal alkoxides such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithium t-butoxide and potassium t-butoxide; sodium hydride; and alkyllithiums such as n-butyllithium, t-butyllithium, sec-butyllithium and methyllithium. The preferred strong base for this reaction is n-butyllithium. The preferred solvent for this reaction is anhydrous tetrahydrofuran. When n-butyllithium is used as the strong base, the reaction is carried out at a temperature of about -35 to about -15 ° C. The benzyl anion is condensed with a benzaldehyde to prepare an intermediate condensation product. The benzaldehyde has the General Formula p-Ri (C6H4) CHO, wherein Ri is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo or amino. Preferably, the benzylic anion is prepared and the condensation product is formed in situ by adding the benzaldehyde to the cold solution of the benzylic anion. The condensation product is treated with an acid chloride to produce an intermediate compound. Representative acid chlorides include acyl chlorides such as acetyl chloride and benzoyl chloride; sulfonyl chlorides such as methanesulfonyl chloride, benzenesulfonyl chloride, 1-butanesulfonyl chloride, ethanesulfonyl chloride, - isopropylsulfonyl chloride and p-toluenesulfonyl chloride; alkoxycarbonyl chlorides such as methoxycarbonyl chloride and benzyloxycarbonyl chloride; and dialkylaminocarbonyl chlorides, such as N, N-dimethylaminocarbonyl chloride; preferably a sulfonyl chloride is used. Preferably, methanesulfonyl chloride is added to the reaction mixture shortly after the condensation product has been formed. This intermediate compound is reacted with a strong second base to produce a styrylsulfide of the Formula VIIIZ, wherein Ri, R2 and R3 are as previously defined. Suitable strong bases for this reaction include metal alkoxides such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithium t-butoxide and potassium t-butoxide.; sodium hydride; alkyllithiums such as n-butyllithium, t-butyllithium, sec-butyllithium and methyllithium; and metal amides such as sodium amide, magnesium diisopropylamide and lithium diisopropylamide. The preferred strong base for this reaction is potassium t-butoxide. Generally, this reaction is carried out at a temperature of about 15 ° C to about room temperature, preferably at room temperature.

- - The styrylsulphide is oxidized to prepare the corresponding styryl sulfoxide. Suitable oxidizing agents for this reaction are peracids such as peracetic acid and m-chloroperoxybenzoic acid, organic peroxides such as t-butyl peroxide; and hydrogen peroxide. Preferably, the oxidizing agent is peracetic acid. This oxidation is typically carried out in an organic solvent such as toluene, benzene, xylene, methanol, ethanol, methyl acetate, ethyl acetate, methylene chloride, 1,2-dichloroethane or chloroform; preferably in methylene chloride. This oxidation can be carried out at a temperature of about -40 to about 0 ° C. Alternatively, when R3 has a tertiary carbon atom adjacent to the sulfur atom, the benzylsulfide intermediate (compound of Formula X) can be used to produce a mixture of E and Z isomers of styryl sulphoxides, which are compounds of Formula II. This synthesis is indicated in Scheme 3.

Scheme 3 The benzylsulfide prepared in the manner described above is oxidized to produce the corresponding benzylsulfoxide. This benzyl sulfoxide is reacted with a strong base and the resulting anion is condensed with a benzaldehyde. The condensation product is reacted with an acid chloride and the resulting intermediate is reacted with a strong second base to produce styryl sulfoxide. The benzylsulfide of Formula X wherein R 2 is as defined above and R 3 is an alkyl radical of 2 to 10 carbon atoms, heat-labile or unstable to acid, alkenyl of 4 to 10 carbon atoms or aryl (alkyl of 1 to 10 atoms) carbon) having a tertiary carbon atom adjacent to the sulfur atom, is oxidized to produce the corresponding -benzylsulfoxide of Formula XI. Oxidizing agents suitable for this reaction are peracids such as peracetic acid and m-chloroperoxybenzoic acid; organic peroxides such as t-butyl peroxide; and hydrogen peroxide. Preferably, the oxidizing agent is peracetic acid. This oxidation is typically carried out in an organic solvent such as toluene, benzene, xylene, methanol, ethanol, methyl acetate, ethyl acetate, methylene chloride, 1,2-dichloroethane or chloroform; preferably at a temperature of about -30 to about 5 ° C. The benzyl sulfoxide of Formula XI wherein R2 and R3 are as defined above, is reacted with a strong base to produce a benzylic anion. Suitable strong bases for this reaction include the metal alkoxides such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithium t-butoxide and potassium t-butoxide; sodium hydride; alkyllithiums such as n-butyllithium, t-butyllithium, sec-butyllithium and methyllithium; and metal amides such as sodium amide, magnesium diisopropylamide and lithium diisopropylamide. The preferred base for this transformation is n-butyllithium. This deprotonation reaction is carried out in an anhydrous organic solvent such as tetrahydrofuran or - 1,2-dimethoxyethane at a temperature of about -25 ° C. The benzylic anion is condensed, without being isolated, with a benzaldehyde compound of the formula pR (C6H4) CHO, wherein Ri is as defined above. Preferably about one equivalent of benzaldehyde is added to the solution prepared as described in the previous paragraph. The diastereomeric mixture resulting from condensation products can be isolated, or preferably used in the next step without isolation. The condensation product is reacted with an acid chloride to produce an intermediate compound. The condensation product is optionally treated with a base such as n-butyllithium and reacted with acid chloride. Representative acid chlorides include acyl chlorides such as acetyl chloride and benzoyl chloride; sulfonyl chlorides such as methanesulfonyl chloride, benzenesulfonyl chloride, 1-butanesulfonyl chloride, ethanesulfonyl chloride, isopropylsulfonyl chloride and p-toluenesulfonyl chloride; alkoxycarbonyl chlorides such as methoxycarbonyl chloride and benzyloxycarbonyl chloride; and dialkylaminocarbonyl chlorides, such as N, N-dimethylaminocarbonyl chloride; preferably a sulfonyl chloride is used. The acid chloride is added to the cold reaction mixture, then the resulting mixture is allowed to reach room temperature. Preferably, methanesulfonyl chloride is added to the reaction mixture shortly after the condensation product has been formed, which eliminates the need to add an additional amount of the base. The resulting intermediate compound is reacted with a strong second base to produce the styrylsulphoxides E and Z of Formula II, wherein Ri, R2 and R3 are as previously defined.

Representatives of the strong second base for this elimination reaction include metal alkoxides such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithium t-butoxide and potassium t-butoxide; sodium hydride; alkyllithiums such as n-butyllithium, t-butyllithium, sec-butyllithium and methyllithium; and metal amides such as sodium amide, magnesium diisopropylamide and lithium diisopropylamide. The preferred base for this transformation is potassium t-butoxide. Preferably an excess of 20% is added, for example 1.2 equivalents. Generally, this reaction is carried out at a temperature of about 15 ° C to about room temperature, preferably at room temperature. The compounds of the present invention can be prepared from compounds of Formula II. The novel sulfenate silylesters are prepared from styryl sulphoxides as shown in Scheme 4. Scheme 4 Generally, the sulfenate silylesters in which Ri, R2 and R7 are as defined above and R3 is an alkyl radical of 1 to 10 carbon atoms thermolabile or unstable to the acid, alkenyl of 4 to 10 carbon atoms or aryl ( 1 to 10 carbon atoms), is prepared by reacting a compound of the Formula II with a silylating reagent. Suitable solvents for this reaction include benzene, toluene, xylene and halogenated high-boiling hydrocarbon solvents, having a boiling point greater than or equal to 80 ° C, such as - - 1, 1, 2-trichloroethane. Suitable silylating reagents include bis (trialkylsilyl) ureas, such as 1,3-bis (trimethylsilyl) urea, 1,3-bis (triethylsilyl) urea, 1,3-bis (dimethylisopropylsilyl) urea, 1,3-bis ( t-butyldimethylsilyl) urea, bis (triarylsilyl) ureas, such as 1,3-bis (triphenylsilyl) urea; bis (dialkylarylsilyl) ureas, such as 1,3-bis (diphenylmethylsilyl) urea; and hexaalkyldisilyl canenes, such as hexamethyldisilylzan; or a combination of a hexaalkyldisilylzan with a catalytic amount of a chlorotrialkylsilane, such as chlorotrimethylsilane. For best results, the final concentration, after completion of the addition, of the compound of Formula II is from about 0.001 M to about 0.5 M. Preferably a slight excess, for example 10%, is used. This reaction can be carried out at a temperature of about 80 to about 140 ° C for about 10 minutes to about 2 hours. Because the Z-isomer reacts much faster than the corresponding E-isomer, the use of only the Z-isomer as a raw material requires less time to complete the transformation.

- - The novel sulfenamides are prepared from the sulfenate silylesters as shown in Scheme 5. Scheme 5 Generally, the silynester of sulfenate wherein Ri, R2 and 7 are as defined above, is prepared from the styryl sulfoxide and, preferably without isolation or purification, is reacted with an amine of the formula HNR5R6, wherein R5 and R $ are as previously defined. Typically, the sulfenate silylester is prepared, the reaction mixture is cooled to a temperature of about 0 to about 50 ° C and treated with the amine. Preferably, one to two equivalent of the amine is used. The transformation of the silyl ester into sulfenamide typically terminates after about 2 to about 8 hours. The resulting sulfenamides can be purified using conventional organic techniques such as silica gel chromatography. The novel disulfides are prepared from the sulfenate silylesters as shown in Scheme 6. Scheme 6 Generally, the silyl ester of sulfenate wherein Ri, R2 and R7 are as defined above, is prepared from styryl sulfoxide and, preferably without isolation or purification, is reacted with a mercaptan of the Formula HSRβ, wherein Rβ is as previously defined, in the presence of an amine base. Preferably, the sulfenate silylester is prepared, the reaction mixture is allowed to cool to room temperature and then treated with a solution containing the mercaptan and the amine base. The solvent for this mercaptan / amine solution is the same as the reaction mixture containing the sulfenate silylester. Representative amine bases - - include triethylamine, diisopropylethylamine, pyridine, morpholine, N-methylmorpholine and collidine. The transformation of the silyl ester into sulfenamide typically terminates after about 1 to about 8 hours. The resulting disulfides can be purified using standard organic techniques such as silica gel chromatography. The silyl ester, sulfenamide and disulfide intermediates are useful for the synthesis of 2-arylbenzo [b] thiophenes, as shown in Scheme 7. Scheme 7 Generally, sulfenate silylesters, sulfenamides or disulfides are treated with acid catalysts to produce the compounds of Formula I. Acid catalysts suitable for this reaction include Lewis acids or Brónsted acids. Representative Lewis acids include zinc chloride, zinc iodide, aluminum chloride and aluminum-bromide. Representative Brónsted acids include: inorganic acids such as sulfuric and phosphoric acid; carboxylic acids such as trifluoroacetic acid; sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, 1-naphthalenesulfonic acid, 1-butanesulfonic acid, ethanesulfonic acid, 4-ethylbenzenesulfonic acid, 1-hexansulfonic acid, 1,5-naphthalenedisulfonic acid, 1-octanesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid; and polymeric arylsulfonic acids such as Nafion, Amberlyst® or Amberlite. The most preferred acid catalysts are sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid and p-toluenesulfonic acid. The most preferred acid catalyst is p-toluenesulfonic acid. Typically, a solution of the acid catalyst in an organic solvent such as toluene, benzene, xylene or a high-boiling halogenated hydrocarbon solvent such as 1,1,2-trichloroethane, is heated to a temperature of about 80 to about 140 °. C and treated with a solution of the silyl ester of sulfenate, sulfenamide or disulfide in the same solvent. An excess of the acid catalyst is used, preferably 3 equivalents of the acid. For best results, the final concentration of the raw material is from about 0.01 M to about 0.2 M, preferably 0.05 M. In addition, better yields are obtained when the sulfenate silylester is added slowly to the acid solution in hot, in a period of about 15 minutes to about 3 hours. For best results, the wastewater is removed from the reaction solution using a Dean-Stark trap or Soxhlet extractor. The styrylsulphoxides are also useful for the preparation of a benzothiophene styrylsulphide, as shown in Scheme 8. Scheme 8 These benzothiophene styryl sulphides, in which Ri and R2 are as defined above, are prepared from styryl sulphoxides. Generally, a styryl sulfoxide solution in which Ri and R2 are as defined above, and R3 is an alkyl radical of 1 to 10 carbon atoms thermolabile or unstable to the acid, alkenyl of 4 to 10 carbon atoms or aryl (alkyl) of 1 to 10 carbon atoms), is added to a solution of an acid catalyst, at a temperature of about 100 to about 140 ° C, wherein the acid catalyst is as defined above. The concentration of the acid catalyst depends on the final concentration of the compound of Formula II and the rate of addition of the compound of Formula II. When the styryl sulfoxide has a final concentration of about 0.2 M and is added over a period of 6 hours, the concentration of the acid is about 0.002 M. When the styryl sulfoxide has a final concentration of about 0.05 M and is added over a period of 30 minutes, the concentration of the acid is about 0.025 M. Significant amounts of the compounds of Formula VI are present in the reaction after about 1 to 2 hours. Longer reaction times produce compounds of Formula I. These compounds of Formula VI can subsequently be converted to compounds of Formula I by an additional acid treatment, such as an amount of about 0.5 to about 3 equivalents and heating to a temperature of about 100 to about 140 ° C. The concentration of the compound of Formula VI is in the range of about 0.01 M to about 0.5 M. Suitable solvents for the formation of the compounds of Formula VI and for their transformation into compounds of Formula I, include toluene, xylene and 1,2-dichloroethane. The compounds of Formula I are useful as intermediates in the synthesis of a series of 3-aroyl-3-arylbenzo [b] thiophenes. U.S. Patent Nos. 4,133,814 and 4,418,068, which are incorporated herein by reference, describe these 3-aroyl-2-arylbenzo [b] thiophenes, as well as methods for their preparation from compounds of Formula I. A synthesis improved from a group of these 3-aroyl-3-arylbenzo.b] thiophenes from compounds of the Formula I, wherein Ri and R 2 are hydrogen, alkoxy of 1 to 4 carbon atoms or arylalkoxy, is illustrated in Scheme 9.

- - Scheme 9 The compound of Formula I wherein Ri and R 2 are hydrogen atoms, alkoxy radicals of 1 to 4 carbon atoms or arylalkoxy, is acylated with the compound of Formula XII wherein R 13 is chloro or hydroxy, in the presence of trichloride boron or boron tribromide; boron trichloride is preferred. The reaction can be carried out in a variety of organic solvents such as chloroform, methylene chloride, 1,2-dichloroethane, 1,2,3-dichloropropane, 1,1,2,2-tetrachloroethane, 1,2-dichlorobenzene , chlorobenzene and fluorobenzene. The preferred solvent for this synthesis is 1,2-dichloroethane. The reaction is carried out at a temperature of about -10 to about 25 ° C, preferably at 0 ° C. The reaction is best carried out at a benzothiophene concentration of Formula I from about 0.2 to about 1.0 M. The acylation reaction generally ends after about 2 to about 8 hours. When Ri and / or R2 is an alkoxy or arylalkoxy radical of 1 to 4 carbon atoms, the acylated benzothiophene is preferably transformed into a compound of Formula XIII wherein R5 and / or Rβ are hydroxy radicals, without isolating the product from the acylation reaction. This transformation is carried out by adding an additional amount of boron trichloride or boron tribromide and heating the reaction mixture. Preferably, 2 to 5 molar equivalents of boron trichloride are added to the reaction mixture, more preferably 3 molar equivalents are added. This reaction is carried out at a temperature of about 25 to about 40 ° C, preferably at 35 ° C. The reaction generally ends after about 4 to about 48 hours. The acylation reaction or the acylation / dealkylation reaction is stopped with an alcohol or a mixture of alcohols. Suitable alcohols for stopping the reaction include methanol, ethanol and isopropanol. Preferably, the acylation / dealkylation reaction mixture is added to a mixture of 95: 5 - of ethanol and methanol (3A ethanol). The 3A ethanol may be at room temperature or it may be heated to reflux, preferably to reflux. When the reaction is stopped in this manner, the compound of Formula XIII conveniently crystallizes from the resulting alcohol mixture. Generally, 1.25 to 3.75 ml of alcohol are used per millimole of the initial benzothiophene. The following examples further illustrate the present invention. The examples are not intended to limit the scope of the invention in any way, and should not be considered in this manner. All experiments were carried out under positive pressure of anhydrous nitrogen. All solvents and reagents were used as purchased. The percentages were generally calculated on a weight basis (w / w); except for high performance liquid chromatography (HPLC) solvents, which were calculated on a volume basis (v / v). The proton nuclear magnetic resonance (H NMR) spectra and the 13 13 nuclear magnetic resonance spectra of C (C NMR) were obtained on a Bruker AC-300 FTNMR spectrometer at 300.135 MHz or at 75.469 MHz for proton and carbon, respectively. or on a GE QE-300 spectrometer at 300.15 MHz. Rapid chromatography on silica gel was carried out as described by Still et al. , using - - silica gel 60 (230-400 mesh, E. Merck). Still et al. , J. Org. Chem. , 43, 2923 (1978). The elemental analyzes for carbon, hydrogen and nitrogen were determined in a Control Equipment Corporation 440 Elemental Analyzer. The elemental analyzes for sulfur were determined in a Brinkman colorimetric elemental analyzer. The melting points were determined in open glass capillaries in a melting point apparatus Mel-Temp II or in an Mettler FP62 automatic instrument and were not corrected. The field mass desorption spectra (EDMC) were obtained using a Varian Instruments mass spectrometer VG 70-SE or VG ZAB-3F. The high-resolution free atom mass bombardment spectra (EBMAL) were obtained using a Varian Instruments VG ZAB-2SE mass spectrometer. The in-yields of 6-methoxy-2- (4-methoxyphenyl) -benzo [b] thiophene were determined by high performance liquid chromatography (HPLC)., compared to an authentic sample of this compound prepared by the synthetic routes already published. See U.S. Patent No. 4,133,814. Generally, the samples of the reaction mixture were diluted with acetonitrile and the diluted sample was evaluated by HPLC using a Zorbax RX-C8 column (4.6 mm x 25 cm) with UV detection (280 nm). The following linear gradient solvent system was used for this analysis: Solvent Gradient System Time (min) A (% B (%) 0 50 50 2 50 50 20 20 80 35 20 80 37 50 50 4455 5500 50 A: aqueous solution of 0.01 M sodium phosphate (pH 2.0) B: acetonitrile The quantity (percentages) of 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) benzoyl] benzo hydrochloride [b] Thiophene in crystalline material (potency) was determined by the following method: A sample of the crystalline solid (5 mg) was weighed into a 100 ml volumetric flask and dissolved in a 70/30 (v / v) mixture of sodium 75 mM sodium phosphate (pH 2.0) and acetonitrile An aliquot of this solution (10 ml) was assayed by high performance liquid chromatography using a Zorbax® RX-C8 column (25 cm x 4.6 mm ID, 5 m particle) and detection UV (280 nm) The following solvent gradient system was used: - - Solvent Gradient System (Power) Time (min) A (%) B (%) 0 70 30 12 70 30 14 25 75 16 70 30 25 70 30 A: 75 mM KH2PO4 buffer (pH 2. 0) B: acetonitrile The percentage of 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) benzoyl] benzo [b] thiophene hydrochloride in the sample was calculated using the area under the peak, the slope (m), and the intercept point (b) of the calibration curve with the following equation: % power = area under the peak - b x volume of the sample (ml) m weight of the sample (mg) The amount (percentages) of solvent, such as 1,2-dichloroethane, present in the crystalline material was determined by gas chromatography. A sample of the crystalline solid (50 mg) was weighed into a 10 ml volumetric flask and dissolved in a solution of 2-butanol (0.025 mg (ml) in dimethyl sulfoxide.) A sample of this solution was analyzed in a gas chromatograph. using a DB Wax column (30 mx 0.53 mm ID, 1 m particle), with a flow in the column of 10 ml / min and detection of flame ionization.The column was heated to a temperature of 35 to 230 ° C for a period of period of 12 minutes The amount of solvent was determined by comparison with the internal standard (2-butanol) EXAMPLE 1 E-4,4'-t-butyl dimethoxystilbenylsulfoxide A. Preparation of E-4, 4'-dimethoxystil- t-butyl benylsulfide A solution of deoxyanisoin (12.82 g) in tetrahydrofuran (100 ml) was treated with titanium (IV) chloride (10.43 g), during the trickle addition of titanium (IV) chloride, the reaction mixture it was cooled to keep the temperature below 35 ° C. At the conclusion of the addition, The resulting mixture was stirred at 30 ° C. After an additional period of 30 minutes, this mixture was treated with a solution of 2-methyl-2-propanethiol (6.76 ml) and triethylamine (16.70 ml) in tetrahydrofuran (15 ml). The resulting mixture was stirred at 50248C. After 2 hours, the mixture was added to a 10% sodium carbonate solution (500 ml). The resulting mixture was extracted with methylene chloride. The methylene chloride extracts were combined and the combined mixture was washed over magnesium sulfate, filtered and concentrated in vacuo to obtain 17.2 g of an oil, which crystallized upon cooling to room temperature. This crystalline material was recrystallized from hot ethanol to obtain 12.3 g of the title compound. Melting point 71-73 ° C. Analysis calculated for C20H24O2S: C, 73.13; H, 7. 36; S, 9.76. Found: C, 73.37; H, 7.51; S, 9.87. B. Preparation of E-4, 4'-dimethoxystyyl-benzylsulfoxide of t-butyl The crystalline compound prepared in the manner described in Example IA was dissolved in toluene (150 ml) and the resulting solution was cooled to about -20 ° C. . The cold solution was treated with peracetic acid (32% w / w in dilute acetic acid, 1.24 g) for 10 minutes. The resulting mixture was extracted with a saturated solution of sodium sulfite and with brine. The organic phase was concentrated in vacuo. The residue was recrystallized from ethyl acetate / heptane, to obtain 14. 11 g of the title compound. Melting point 104 ° C (with decomposition). Analysis calculated for C20H24O2S: C, 69.74; H, 7.02; S, 9.31.

Found: C, 69.47; H, 7.04; S, 9.54. EXAMPLE 2 Z-4, 4'-t-butyl dimethoxystilbenylsulfoxide A. Preparation of t-butyl 4-dimethoxystilbenylsulfide A mixture of 4-methoxybenzyl alcohol (10.13 g) and zinc iodide (11.7 g) in 1,2-dichloroethane (120 ml) was treated with 2-methyl-2-propanothiol (9.92 ml) in a single portion. The resulting mixture was stirred at room temperature. After about 18 hours, the reaction mixture was diluted with water (100 ml) and with methylene chloride (100 ml). The organic phase was removed, dried over magnesium sulfate, filtered and concentrated in vacuo to obtain 14.4 g of an oil. H NMR (CDC13): d 7.28 (d, 2H), 6.85 (d, 2H), 3. 77 (s, 3H), 3.73 (s, 2H), 1.36 (s, 9H). 13 C NMR (CDCl 3): d 130, 114, 56, 35, 32. Analysis calculated for C12H18OS: C, 68.52; H, 8. 63. Found: C, 68.80; H, 8.67. B. Preparation of t-butyl Z-4, 4'-dimethoxystyyl-benzylsulfide A solution of the compound prepared in the manner described in Example 2A (2.51 g) in tetrahydrofuran (50 ml) was cooled to approx. -20 ° C. This cold solution was treated with a solution of n-butyllithium in hexane (1.6 M, 7.47 ml) for 10 minutes. The resulting solution was allowed to reach a temperature of about 0 ° C in a period of 35 minutes. This cold solution was treated with p-anisaldehyde 81.46 ml). After an additional period of 15 minutes, the reaction mixture was treated with methanesulfonyl chloride (0.95 ml). The resulting reaction mixture was allowed to reach room temperature. After an additional 45 minutes, the reaction mixture was treated with a solution of potassium t-butoxide in tetrahydrofuran (1.0 M, 12.0 ml). After an additional 45 minutes, the reaction was stopped by the addition of 1N hydrochloric acid (12.0 ml). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated, to obtain an oil (4.4 g). : H NMR (CDCI3): 7.95 (d, H), 7.05 (s, H), 6.9 (d, H), 6.8 (dd, 2H), 3.75 (s, 3H), 0.95 (s, 9H). 13 C NMR (CDCl 3): d 153, 139, 137, 56, 32. C. Preparation of t-butyl Z-4, 4'-dimethoxystil-benzylsulfoxide The compound of Example 2B was transformed into the title compound using the procedure substantially as described in Example IB.

- - X H NMR (CDCl 3): d 7.61 (d, H), 7.56 (d, H), 7.1 (s, H), 6.9 (dd, 2H), 3.83 (s, 3H), 1.05 (s, 9H). 13, NMR (CDCl 3): d 142, 132.5, 131, 118, 117, 56, 24 Analysis calculated for C20H24O3S: C, 69.74; H, 7. 02 Found: C, 69.98; H, 6.94. EXAMPLE 3 E and Z-4, 4'-t-butyl dimethoxystilbenylsulfoxide A. Preparation of t-butyl 4-methoxybenzylsulfide A mixture of 4-methoxybenzyl alcohol 810.13 g) and zinc iodide (11.7 g) in 1, 2- dichloroethane (120 ml) was treated with 2-methyl-2-propanothiol (9.92 ml) in a single portion. The resulting mixture was stirred at room temperature. After about 18 hours, the reaction mixture was diluted with water (100 ml) and with methylene chloride (100 ml). The organic phase was removed, dried over magnesium sulfate, filtered and concentrated in vacuo to obtain 14.4 g of an oil. H NMR (CDCl 3): d 7.28 (d, 2H), 6.85 (d, 2H), 3.77 (s, 3H), 3.73 (s, 2H), 1.36 (s, 9H). 13 C NMR (CDCl 3): d 130, 114, 56, 35, 32.

- - Analysis calculated for C12H18OS: C, 68.52; H, 8. 63. Found: C, 68.80; H, 8.67 B. Preparation of t-butyl 4-methoxybenzylsulfoxide A solution of the compound prepared in the manner described in Example 3A (14.4 g) in 1,2-dichloroethane (50 ml) was cooled to about 5 ° C and the cold solution it was treated with peracetic acid (32% w / w in dilute acetic acid, 14.2 ml) in a period of 30 minutes. After concluding the addition of the peracetic acid, the reaction mixture was treated with brine and with sodium bicarbonate. The organic phase was removed, dried over magnesium sulfate, filtered and concentrated, to obtain a yellow precipitate. This residue was treated with hexane (100 ml) and the resulting mixture was stirred at room temperature. After approximately 18 hours, the mixture was filtered and the solids were washed with hexane (100 ml). The solid material was dried in vacuo to obtain 14.07 g of the title compound. Melting point 124-126 ° C. X H NMR (CDCl 3): d 7.26 (d, 2 H), 6.89 (d, 2 H), 3.79 (d, H), 3.78 (s, 3 H), 3.58 (d, H), 1.3 (s, 9 H). - - 13 C NMR (CDCl 3): d 132, 114, 56, 53, 23. Analysis calculated for C12H18OS: C, 63. 68; H, 8 02. Found: C, 63.72; H, 7.93. C. Preparation of t-butyl E and Z-4,4'-dimethoxystyylbenzylsulfoxide A solution of the compound prepared in the manner described in Example 3B (10.0 g) in tetrahydrofuran (140 ml) was cooled to a about -30 ° C to about -25 ° C (dry ice / acetone bath). This cold solution was treated with n-butyllithium in cyclohexane (1.6 M, 27.65 ml) for 25 minutes. After stirring for 35 minutes, the reaction mixture was treated with p-anisaldehyde (5.4 ml). The ice / acetone bath was removed and the reaction mixture allowed to warm to about 20 ° C. This mixture was treated with methanesulfonyl chloride (3.5 ml). The temperature of the reaction was raised from about 20 ° C to about 35 ° C by adding the methanesulfonyl chloride. The mixture was cooled to about 25 ° C, then treated with potassium t-butoxide in tetrahydrofuran (1 M, 50.9 ml). After stirring for an additional 35 minutes, the reaction mixture was treated with 1 N hydrochloric acid (51.0 ml). The phases were separated and the organic phase was dried over magnesium sulfate, filtered and concentrated to obtain an oil (16.67 g). This material was used in the next stage without further purification. The carbon and proton NMR spectra were similar to those obtained for the compound prepared in the manner described in Examples 1 and 2. EXAMPLE 4 E and Z-4,4'-trimethylsilyl dimethoxystyylbenylsulfenate A mixture of the compound prepared from the The method described in Example 1 (350 mg) and 1,3-bis (trimethylsilyl) urea (116 mg) in toluene (11 ml) was heated to reflux. After 1.5 hours, the reaction mixture was allowed to cool to room temperature, filtered and the filtrate was concentrated in vacuo to obtain a 7: 1 mixture of the E / Z regioisomers of the title compounds. FDMS: m / z = 361 (M + l). Isomer E: H NMR (dß-benzene): d 7.39 (d, 2H), 7.10 (d, 2H), 6.68 (d, 2H), 6.68 (s, 1H), 6.57 (d, 2H), 3.18 (s, 3H), 3.17 (s, 3H), 0.23 (s, 9H). Isomer Z: - - XH NMR (d6-benzene): d 7.71 (d, 2H), 7.31 (d, 2H), 6.85 (d, 2H), 6.79 (d, 2H), 6.60 (s, 1H), 3.28 (s, 3H), 3.26 (s, 3H), -0.05 (s, 9H). EXAMPLE 5 E and trimethylsilyl trimetilsilyl dimethoxystylbenylsulfoxide A mixture of the compound prepared in the manner described in Example 2 and 1,3-bis (trimethylsilyl) urea in toluene was heated to reflux. After ten minutes, the reaction mixture was allowed to cool to room temperature, filtered and the filtrate was concentrated in vacuo to obtain a 7: 1 mixture of the E / Z regioisomers of the title compounds. Isomer E: 13C NMR (d6-benzene, 8 ° C): d 160.49, 158.53, 141. 54, 131.97, 129.91, 129.65, 125.59, 116.41, 114.68, 113.98, 54.56, -0.09.

EXAMPLE 6 E and Z-4, 4'-dimethoxystylbenylsulfenamide of N, N-dimethyl A mixture of the compound prepared in the manner described in Example 1 (1.74 g) and 1,3-bis (trimethylsilyl) urea (578 mg) in toluene (54 ml), heated to reflux. After 1.5 hours, the reaction mixture was allowed to cool to room temperature, treated with dimethylamine (2.80 ml, 2.0 M in tetrahydrofuran). After an additional 2 hours, the reaction mixture was evaporated to dryness to obtain a 7: 1 mixture of the E / Z regioisomers of the title compound. This residual mixture was purified using flash chromatography on silica gel, eluting with a mixture of ethyl acetate / hexane (9: 1), to obtain 1.06 g of the title compounds as an 8: 1 mixture of the regioisomers E / Z. FDMS: m / z = 315 (M +). Analysis calculated for C18H21NO2S: C, 68. 54; H, 6. 71; N, 4 44 Found: C, 68.40; H, 6.69; N, 4.22. Isomer E: XH NMR (d6-benzene): d 7.44 (d, 2H), 7.11 (d, 2H), 6.99 (s, 1H), 6.71 (d, 2H), 6.56 (d, 2H), 3.22 (s, 3H), 3.18 (s, 3H), 2.66 (s, 6H). 13 C NMR (d6-benzene): d 160.00, 158.83, 139.70, 131.48, 130.78, 130.51, 129.94, 123.77, 114.55, 113.97, 54.63, 54.61, 48.17. Isomer Z: - 1 H NMR (de-benzene): d 7.61 (d, 4H), 7.82 (d, 2H), 6.80 (d, 2H), 6.80 (s, 1H), 3.32 (s, 3H), 3.27 (s, 3H), 2.41 (s, 6H). 13 C NMR (d-benzene): d 159.89, 159.30, 139.76, 136.46, 131.94, 131.82, 130.82, 130.20, 113.76, 54.81, 54.73, 48.61. EXAMPLE 7 E and Z-4,4'-dimethoxystilbenylsulfenamide of N-benzyl A mixture of the compound prepared in the manner described in Example 1 (1.74 g) and 1,3-bis (trimethylsilyl) urea (578 mg) in toluene ( 54 ml), was heated to reflux. After 1.5 hours, the reaction mixture was allowed to cool to room temperature and treated with benzylamine (0.575 ml). After an additional 2 hours, the reaction mixture was evaporated to dryness to obtain a 7: 1 mixture of the E / Z regioisomers of the title compound. This residual mixture was purified using silica gel flash chromatography, eluting with a mixture of ethyl acetate / hexane (7: 1), to obtain 1.06 g of the title compounds as a 6: 1 mixture of the regioisomers E / Z. Analysis calculated for C23H23NO2S: C, 73.18; H, 6.14; N, 3.71.

Found: C, 73.16; H, 6.18; N, 3.50. Isomer E: XH NMR (de-benzene): d 7.41 (d, 2H), 7.13 (d, 2H), 7.12-7.03 (m, 5H), 6.87 (s, 1H), 6.71 (d, 2H), 6.59 (d, 2H), 3.89 (d, 2H), 3.23 (s, 3H), 3.20 (s) , 3H), 2.71 (t, 1H). 13C NMR (de-benzene): d 159.98, 158.91, 140.53, 139. 77, 131.45, 130.50, 129.87, 128.77, 128.66, 128.59, 127.53, 123.10, 114.74, 114.02, 56.14, 54.69, 54.64. Isomer Z: XH NMR (d6-benzene): d 7.59 (d, 2H), 7.53 (d, 2H), 7.01-6.91 (m, 5H), 6.83 (s, 1H), 6.79 (d, 2H), 6.77 (d, 2H), 3.62 (d, 2H), 3.31 (s, 3H), 3.27 (s) , 3H), 2.82 (t, 1H). 13 C NMR (d6-benzene): d 160.05, 159.14, 140.48, 139. 27, 132.50, 131.32, 130.04, 129.86, 128.87, 128.58, 128.46, 127.49, 114.48, 114.00, 56.23, 54.90, 54.78. EXAMPLE 8 6-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene A solution of p-toluenesulfonic acid monohydrate (552 mg) was added to toluene (15 ml) and heated to reflux, stirring the water by means of a trap. Dean-Stark This reflux solution was treated with a solution of the regioisomeric compounds prepared in the manner described in the - - Example 4 (523 mg) in toluene (15 ml) for 15 minutes. After completing the addition, an aliquot was removed for HPLC analysis. This analysis demonstrated a 46.6% in situ yield of the title compound. EXAMPLE 9 6-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene A solution of p-toluenesulfonic acid monohydrate (1.26 g) in toluene (20 ml) was heated to reflux and the water was removed by collecting it in a trap. Dean-Stark A solution of the regioisomers prepared in the manner described in Example 6 (650 mg) in toluene (9 ml) was added to the acid solution at reflux in a period of 1.8 hours. The reaction mixture was treated with ethanol (10 ml) and the resulting mixture was allowed to cool to room temperature. The obtained slurry was stirred at room temperature. After about 18 hours, the mixture was cooled to about 5 ° C and filtered to obtain 290 mg of the title compound. Melting point 199-200 ° C. X H NMR (de-DMSO): d 7.67 (d, 1 H), 7.64 (d, 2 H), 7. 61 (s, 1H), 7.52 (d, 1H), 7.01 (d, 2H), 6.98 (dd, 1H), 3.81 (s, 3H), 3.79 (s, 3H). Analysis calculated for C 16 H 14 O 2 S: C, 71.09; H, 5.22.

Found: C, 71.09; H, 5.27. EXAMPLE 10 E and Z-3- (4,4'-dimethoxystilbenylsulfide) -6-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene A solution of p-toluenesulfonic acid monohydrate (552 mg) in toluene (111 ml. ) and heated to reflux, and the water was removed by collecting it in a Dean-Stark trap. A solution of the compound prepared in the manner described in Example 1 (10 g) in toluene (34 ml) was added to the acid solution at reflux in a period of 6 hours. After an additional 2 hours, the reaction mixture was cooled to 0 ° C. After an additional 18 hours, the cold mixture was filtered to remove precipitated 6-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene. The filtrate was extracted with an equal volume of saturated sodium bicarbonate solution. The organic phase was separated, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 4.8 g of an orange oil. This oil was divided into two parts and each was purified using flash chromatography on silica gel, eluting with hexane / ethyl acetate (3.5: 1). The fractions containing the desired regioisomers were concentrated until an oil was obtained. This oil was treated with diethyl ether to selectively crystallize the regioisomer eluting first (155 mg). The mother liquors of these crystallizations were enriched with the regioisomer that elutes later. Isomer eluting first: XH NMR (CDCI3): d 7.71 (d, 2H), 7.64 (d, 1H), 7.46 (d, 2H), 7.06 (d, 1H), 6.94 (d, 2H), 6.92 (d , 2H), 6.90 (m, 1H), 6.85 (d, 2H), 6.59 (s, 1H), 6.45 (d, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.66 (s, 3H). High resolution FABMS calculated for C32H29O4S2 (MH +) 541.1507. Found: 541.1491 Isomer eluting after:? H NMR (CDCI3): d 7.90 (d, 1H), 7.62 (d, 2H), 7. 24 (1H), 7.08 (d, 2H), 7.02 (dd, 1H), 6.96 (d, 2H), 6.74-6.71 (d, 2H), 6.70 (d, 2H), 6.55 (d, 2H), 6.21 (d, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.76 (s, 3H), 3.67 (s, 3H). FDMS: m / z = 540 (m +). EXAMPLE 11 6-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene The compound (isomer eluting first) prepared in the manner described in Example 10 (125 mg) was added to a refluxing solution of p-acid. toluenesulfonic monohydrate (4.2 mg) in toluene (1.5 ml). After 6 hours, methanesulfonic acid was added (7.5 ml) to the reaction mixture. After an additional hour, the reaction mixture was allowed to cool to room temperature. The resulting mixture was diluted with acetonitrile and evaluated by HPLC, demonstrating a 71.1% in situ yield of the title compound. EXAMPLE 12 6-Hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) -benzoyl] benzo [b] thiophene hydrochloride Solvate in 1,2-dichloroethane A. Preparation of 4- (2- ethyl piperidinoethoxy) benzoate A mixture of ethyl 4-hydroxybenzoate (8.31 g), 1- (2-chloroethyl) piperidine monohydrochloride (10.13 g), potassium carbonate (16.59 g) and methyl ethyl ketone (60 ml) was heated to 80 ° C. After one hour, the reaction mixture was cooled to about 55 ° C and treated with an additional amount of l- (2-chloroethyl) -piperidine monohydrochloride (0.92 g). The resulting mixture was heated to 80 ° C. The reaction was monitored by thin layer chromatography (TLC), using silica gel plates and ethyl acetate / acetonitrile / triethylamine (10: 6: 1 v / v). Additional portions of l- (2-chloroethyl) piperidine hydrochloride were added until the initial 4-hydroxybenzoate ester was consumed. After concluding the reaction, the mixture was treated with water (60 ml) and allowed to cool to room temperature. The aqueous phase was discarded and the organic phase was concentrated in vacuo at 40 ° C and 40 mm Hg. The resulting oil was used in the next step without further purification. B. Preparation of 4- (2-piperidinoethoxy) benzoic acid hydrochloride A solution of the compound prepared in the manner described in Example 12A (about 13.87 g) in methanol (30 ml) was treated with 5 N sodium hydroxide (15 ml. ) and heated to 40 ° C. After 4 1/2 hours water (40 ml) was added. The resulting mixture was cooled to a temperature of 5 ° C to 10 ° C and concentrated hydrochloric acid (18 ml) was slowly added. The title compound crystallized during acidification. This crystalline product was cooled by filtration and dried under vacuum at a temperature of 40 ° C to 50 ° C, to obtain a yield of 83% of the title compound. Melting point 270-271 ° C. C. Preparation of 4- (2-piperidinoethoxy) benzoyl chloride hydrochloride A solution of the compound prepared in the manner described in Example 12B (30.01 g) and dimethylformamide (2 ml) in methylene chloride (500 ml) was treated with oxalyl chloride (10.5 ml) over a period of 30 to 35 minutes. After stirring for about 18 hours, it was evaluated whether the reaction had already been concluded by a CLAR analysis, an additional amount of oxalyl chloride can be added to the reaction mixture if there is still an initial carboxylic acid present. Upon completion, the reaction solution was evaporated to dryness in vacuo. The residue was dissolved in methylene chloride (200 ml) and the resulting solution was evaporated to dryness. This dissolution / evaporation procedure was repeated to obtain the title compound as a solid. D. Preparation of 6-Hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) benzoyl] -benzo [b] thiophene Hydrochloride Solvate in 1,2-dichloroethane A mixture of the compound prepared from the As described in Example 8 or 9 (2.92 g), the compound prepared in the manner described in Example 12C (3.45 g) and 1,2-dichloroethane (52 ml) was cooled to about 0 ° C. Gaseous boron trichloride was condensed in a cold graduated cylinder (2.8 ml) and this condensate was added to the cold mixture described above. After 8 hours at 0 ° C, the reaction mixture was treated with an additional amount of boron trichloride (2.8 ml). The resulting solution was heated to 35 ° C. After 16 hours, the reaction was over.

Methanol (30 ml) was treated with the above reaction mixture over a period of 20 minutes, causing the methanol to reflux. The resulting slurry was stirred at 25 ° C. After one hour, the crystalline product was filtered, washed with cold methanol (8 ml) and dried at 40 ° C under vacuum, to obtain 5.14 g of the title compound. Melting point 225 ° C. Power (HPLC): 86.8% 1,2-dichloroethane (gas chromatography): 6.5% EXAMPLE 13 6-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene A solution of p-toluenesulfonic acid monohydrate (1.05 g) in toluene (20 ml) it was heated to reflux and the water was removed by collecting it in a Dean-Stark trap. A solution of the regioisomeric compounds prepared in the manner described in Example 7 (780 mg) in toluene (9 ml) was added over a period of 10 minutes. After one hour, the reaction mixture was treated with ethanol (10 ml) and the resulting mixture was allowed to cool to room temperature. The resulting slurry was stirred at room temperature. After about 18 hours, the mixture was filtered to obtain 149 mg of the title compound. Melting point 199-200 ° C.

Analysis calculated for C 16 H 14 O 2 S: C, 71.09; H, 5.22. Found: C, 71.05; H, 5.22. EXAMPLE 14 Etyldisulfide of E and Z-4,4'-dimethoxystilbenyl A solution of the regioisomeric compounds prepared in the manner described in Example 4 (1.83 g) in toluene (54 ml) was treated with ethanethiol (0.433 ml) and triethylamine ( 0.715 ml). After about 2.5 hours at room temperature, the reaction solution was evaporated to dryness in vacuo to obtain a mixture of regioisomers. The residue was purified, using chromatography on silica gel, eluting with ethyl acetate / hexane (9: 1), to obtain 1.14 g of a 5.7: 1 mixture of the E / Z regioisomers of the title compounds. Analysis calculated for C 18 H 20 O 2 S 2: C, 65.03; H, 6. 06. Found: C, 65.32; H, 6.28. Isomer E: XH NMR (d6-benzene): d 7.35 (d, 2H), 7.19 (s, 1H), 7.05 (d, 2H), 6.72 (d, 2H), 6.54 (d, 2H), 3.21 (s, 3H), 3.14 (s, 3H), 2.39 (q, 2H), 1.09 (t, 3H) ). 13C NMR (de-benzene): d 160-09, 159.16, 135.95, 131. 71, 130.61, 130.16, 12.48, 126.88, 114.54, 113.99, 54.64, 54.61, 32.29, 14.33. Isomer Z:: H NMR (dß-benzene): d 7.67 (d, 2H), 7.58 (d, 2H), 6.90 (s, 1H), 6.83 (d, 2H), 6.80 (d, 2H), 3.30 (s, 3H), 3.28 (s, 3H), 2.26 (q, 2H), 0.94 (t, 1H) ). 13C NMR (de-benzene): d 159.98, 159.53, 137.58, 134.03, 132.79, 131.69, 130.45, 113.91, 113.87, 54.79, 54.73, 32.61, 14.25. EXAMPLE 15 6-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene A solution of p-toluenesulfonic acid monohydrate (1.21 g) in toluene (20 ml) was heated to reflux and the water was removed by collecting it in a trap. Dean-Stark To the acid reflux solution was added a solution of the regioisomeric compounds prepared in the manner described in Example 14 (685 mg, regioisomeric mixture 5.7: 1) in toluene (9 ml) over a period of 1.8 hours. An aliquot of the mixture was analyzed by HPLC, demonstrating a 23.2% in situ yield of the title compound. 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 an antecedent, what is contained in the following is claimed as property.

Claims

CLAIMS A compound of the Formula characterized in that: Ri is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo or amino; R2 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo or amino; R is a radical 0 Si (R) 3, NR 5 R 6 or SRβ; each R is independently an alkyl, aryl, or arylalkyl radical of 1 to 6 carbon atoms; R5 and Rβ are independently a hydrogen atom, an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms; or R5 and R together with the nitrogen atom form a ring which is selected from the group consisting of piperidine, pyrrolidine, morpholine or hexa ethylimine; and Rβ is an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms;
2. The compound according to claim 1, characterized in that: R 1 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, or arylalkoxy; and R2 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, or arylalkoxy.
3. The compound according to claim 2, characterized in that: R4 is a radical 0Si (R) 3; and each R is independently an alkyl, aryl, or arylalkyl radical of 1 to 6 carbon atoms.
4. The compound according to claim 3, characterized in that R4 is OTMS, OTES, OTIPS, ODMIPS, ODEIPS, OTDS, OTBDMS, OTBDPS, OTBS, OTPS, ODPMS, or OTBMPS.
5. The compound according to claim 4, characterized in that R4 is OTMS, OTES, ODMIPS, ODEIPS, OTBDMS, OTBS, or OTPS.
6. The compound according to claim 5, characterized in that Ri and R2 are an alkoxy radical of 1 to 4 carbon atoms.
7. The compound according to claim 6, characterized in that Ri and R2 are methoxy radicals and R4 is an OTMS radical.
8. The compound according to claim 2, characterized in that: R4 is NR5R6; and R5 and Re are independently a hydrogen atom, an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms, or R5 and Re together with the nitrogen atom form a ring that is selected from the group consisting of piperidine, pyrrolidine , morpholine or hexamethylimine.
9. The compound according to claim 8, characterized in that R5 and R are independently a hydrogen atom, an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms, or R5 and Rβ together with the nitrogen atom form a ring that is selected from the group consisting of piperidine and pyrrolidine.
10. The compound according to claim 9, characterized in that Ri and R2 are an alkoxy radical of 1 to 4 carbon atoms.
11. The compound according to claim 10, characterized in that Ri and R2 are methoxy radicals, and R5 and Rβ are methyl radicals.
The compound according to claim 10, characterized in that Ri and R2 are methoxy radicals, R5 is a hydrogen atom and Rβ is a benzyl radical.
13. The compound according to claim 2, characterized in that: R is SRβ; and Rβ is an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms.
The compound according to claim 13, characterized in that Rβ is an alkyl or arylalkyl radical of 1 to 6 carbon atoms.
15. The compound according to claim 14, characterized in that Rβ is an alkyl radical of 1 to 6 carbon atoms.
16. The compound according to claim 15, characterized in that Ri and R2 are alkoxy radicals of 1 to 4 carbon atoms.
17. The compound according to claim 16, characterized in that Ri and R2 are methoxy radicals and Re is an ethyl radical.
18. A process for preparing a compound of the Formula characterized in that: Ri is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo or amino; R2 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo or amino; R4 is a radical 0Si (R) 3, NR5R6 or SRβ; each R is independently an alkyl, aryl, or arylalkyl radical of 1 to 6 carbon atoms; R5 and Re are independently a hydrogen atom, an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms; or R5 and Rβ together with the nitrogen atom form a ring that is selected from the group consisting of piperidine, pyrrolidine, morpholine or hexamethylimine; and Rβ is an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms; which comprises: (1) reacting a compound of the Formula (2) wherein: Ri and R2 are as defined above, and R3 is an alkyl radical of 2 to 10 carbon atoms, thermolabile or unstable to the acid, alkenyl of 4 to 10 carbon atoms, or aryl (alkyl of 1 to 10 carbon atoms). carbon); with a silylating reagent to produce a sulfenate silyl ester of the Formula where: Rl and R2 are as previously defined; R7 is a radical 0Si (R) 3, - and each R is independently an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms: (2) optionally, reacting the silynester of sulfenate with an amine of the Formula HNR5R6, wherein R5 and Rβ are as previously defined; or (3) optionally reacting the sulfenate silanester with a mercaptan of the Formula HSRβ, wherein Rβ is as previously defined, in the presence of an amine base.
19. The process according to claim 1, for preparing a compound of the Formula characterized in that: R 1 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo or amino; R2 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo or amino; R7 is a radical OSi (R) 3; and each R is independently an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms; which comprises reacting a compound of the Formula wherein: R1 and 2 are as defined above, and R3 is an alkyl radical of 2 to 10 carbon atoms thermolabile or unstable to the acid, alkenyl of 4 to 10 carbon atoms or aryl (alkyl of 1 to 10 carbon atoms) ); with a silylation reagent.
20. The process according to claim 19, characterized in that: R 1 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms or arylalkoxy; and R2 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms or arylalkoxy.
21. The process according to claim 20, characterized in that: R7 is OTMS, OTES, OTIPS, ODMIPS, ODEIPS, OTDS, OTBDMS, OTBDPS, OTBS, OTPS, or OTBMPS.
22. The process according to claim 21, characterized in that the silylating reagent is a bis (trialkylsilyl) urea, or a combination of a hexaalkyldisilyl azan and a catalytic amount of a chlorotrialkylsilane and R is an alkyl radical of 1 to 6 carbon atoms. carbon.
23. The process according to claim 22, characterized in that the silylating agent is a bis (trimethylsilyl) urea and R is methyl.
24. The process according to claim 23, characterized in that R3 is an alkyl radical of 2 to 10 carbon atoms thermolabile or unstable to the acid.
25. The process according to claim 24, characterized in that Ri and R2 are methoxy radicals and R3 is a t-butyl radical.
26. The process according to claim 18 for the preparation of a compound of the Formula characterized in that: R1 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo, amino; R2 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo, amino; and R5 and Rβ are independently a hydrogen atom, an alkyl, arylalkyl or aryl radical of 1 to 6 carbon atoms; or R5 and Rβ together with the nitrogen atom form a ring that is selected from the group consisting of piperidine, pyrrolidine, morpholine or hexamethylimine; comprising the steps of: (1) reacting a compound of the Formula wherein: Ri and R2 are as defined above, and R3 is an alkyl radical of 2 to 10 carbon atoms, thermolabile or unstable to the acid, alkenyl of 4 to 10 carbon atoms, or aryl (alkyl of 1 to 10 carbon atoms). carbon); with a silylating reagent to produce a sulfenate silyl ester of the Formula where: Ri and R2 are as previously defined; R7 is a radical 0Si (R) 3, - and each R is independently an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms; and (2) reacting the sulfenate silyl ester with an amine of the formula HNR5R6, wherein R5 and R are as defined above.
27. The process according to claim 26, characterized in that: R1 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms or arylalkoxy; and R2 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms or arylalkoxy.
28. The process according to claim 27, characterized in that the silylating agent is a bis (trimethylsilyl) urea and R is methyl.
29. The process according to claim 28, characterized in that R3 is an alkyl radical of 2 to 10 carbon atoms thermolabile or unstable to the acid.
30. The process according to claim 29, characterized in that Ri and R2 are methoxy radicals and R3 is a t-butyl radical.
31. The process according to claim 30, characterized in that R5 and R are independently a hydrogen atom, an alkyl or aryl radical of 1 to 6 carbon atoms.
32. The process according to claim 31, characterized in that R5 and Rβ are methyl, or R5 is a hydrogen atom and Rβ is benzyl.
33. The process according to claim 18 for the preparation of a compound of the Formula XIV R1 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo, amino; R2 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo, amino; and Rβ is an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms; comprising the steps of: (1) reacting a compound of the Formula wherein: Ri and R2 are as defined above, and R3 is an alkyl radical of 2 to 10 carbon atoms, thermolabile or unstable to the acid, alkenyl of 4 to 10 carbon atoms or aryl (alkyl of 1 to 10 carbon atoms) ); with a silylating reagent, to produce a sulfenate silyl ester of the Formula where: Rl and 2 are as previously defined; R7 is a radical 0Si (R) 3, - and each R is independently an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms; and (2) reacting the silynester of sulfenate with a mercaptan of the Formula HSRβ, wherein Rβ is as previously defined, in the presence of an amine base.
34. The process according to claim 33, characterized in that: R1 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms or arylalkoxy; and R2 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms or arylalkoxy.
35. The process according to claim 34, characterized in that the amine base is triethylamine, diisopropylethylamine or pyridine.
36. The process according to claim 35, characterized in that the silylating agent is a bis (trimethylsilyl) urea and R is methyl.
37. The process according to claim 36, characterized in that R3 is an alkyl radical of 2 to 10 carbon atoms thermolabile or unstable to the acid.
38. The process according to claim 37, characterized in that the amine base is triethylamine.
39. The process according to claim 38, characterized in that Ri and R2 are methoxy radicals and R3 is a t-butyl radical.
40. The process according to claim 39, characterized in that Re is an alkyl radical of 1 to 6 carbon atoms.
41. The process according to claim 40, characterized in that Rβ is ethyl.
42. A process for the synthesis of a compound of the Formula characterized in that: R9 is a hydrogen atom, a halo, amino or hydroxyl radical; Rio is a hydrogen atom, a halo, amino or hydroxyl radical; Rll and R12 are independently an alkyl radical of 1 to 4 carbon atoms, or Rn and Ri2 together with the adjacent nitrogen atom form a heterocyclic ring which is selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino and morpholino; and HX is HCl or HBr; comprising the steps of: (a) performing the cyclization, in the presence of an acid catalyst, of a compound of the Formula wherein: R 1 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo or amino; R2 is a hydrogen atom, an alkoxy radical of 1 to 4 carbon atoms, arylalkoxy, halo or amino; and R is a radical OSi (R) 3, NR5R6 or SRβ; each R is independently an alkyl, aryl, or arylalkyl radical of 1 to 6 carbon atoms; R5 and R are independently a hydrogen atom, an alkyl radical, or aryl of 1 to 6 carbon atoms; or R5 and RI together with the nitrogen atom form a ring that is selected from the group consisting of piperidine, pyrrolidine, morpholine or hexamethylimine; Rβ is an alkyl, aryl or arylalkyl radical of 1 to 6 carbon atoms; to prepare a benzothiophene compound of the Formula where Ri and R2 are as previously defined; (b) acylating the benzothiophene compound with an acylating agent of the Formula XII where: Rll. R12 and HX are as previously defined; and R13 is a chloro, bromo or hydroxyl radical; in the presence of BX'3, wherein X 'is chlorine or bromine; (c) when Ri and / or R2 is an alkoxy or arylalkoxy radical of 1 to 4 carbon atoms, one or more phenolic groups of the acylation product of step (b) are dealkylated by further reaction with BX'3, where X 'is like the one previously defined; and (d) isolating the compound of Formula XIII.