MXPA97009239A - Process for the synthesis of benzo [b] tiofe - Google Patents

Abstract

The present invention is directed to a novel process for the synthesis of 2-aryl benzo [b] thiophenes, and to a new intermediate for the same.

Description

PROCESS FOR THE SYNTHESIS OF BENZO [b] TIOFENES DESCRIPTION OF THE INVENTION The present invention is directed to a new process 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 acid catalyzed cyclization of dialkyl acetals of 2-phenylthioacetaldehyde. The unsubstituted benzo [b] thiophenes are prepared by catalytic condensation of styrene and sulfur. Benzo [b] thiophenes substituted at position 3 are prepared by acid catalyzed cyclization of arylthiomethyl ketones; however, this route is limited to the preparation of 3-alkyl benzo [b] thiophenes. See Campaigne, "Thiophenes and their Benzo Derivatives: (iii) Synthesis and Applications," in Comprehensive Heterocyclic Chemistry (Katritzky and Rees, eds.), Volume IV, Part III, 863-934 (1984). 3-Chloro-2-phenylbenzo [b] thiophene is prepared by the reaction of diphenylacetylene with sulfur dichloride. Barton and Zika, J. Org. Chem., 35, 1729-1733 (1970). The benzo [b] thiophenes REF: 26061 have also been prepared by pyrolysis of styryl sulfoxides. However, low yields and extremely high temperatures make this route unsuitable for the production scale synthesis. See Ando, J. Chem. Soc., Chem. Comm., 704-705 (1975). The preparation of 6-hydroxy-2- (4-hydroxyphenyl) -benzo [b] thiophenes was described in U.S. Patent Nos. 4,133,814 and 4,380,635. A process described in these patents is the intra-molecular cyclisation / rearrangement catalyzed by acid of α- (3-methoxyphenylthio) -4-methoxyacetophenone. Reaction of this starting compound in pure phosphoric acid at about 85 ° C to about 90 ° C gives an approximate 3: 1 mixture of two regioisomeric products: 6-methoxy-2- (4-methoxyphenyl) benzo [b ] thiophene and 4-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene. These isomeric benzo [b] -thiophenes co-precipitate from the reaction mixture, producing a mixture containing both compounds. To obtain an individual regioisomer, the regioisomers must be separated such as by chromatography or fractional crystallization. Therefore, there is presently a need for an efficient and regiospecific synthesis of 2-aryl benzo [b] thiophenes from readily available raw materials.

The present invention is directed to a process for the synthesis of benzo [b] thiophenes. Specifically, the present invention is directed to a process for preparing a compound of the formula: wherein: Ri is hydrogen, alkoxy of 1 to 4 carbon atoms, arylalkoxy, halo, amino; and R2 is hydrogen, alkoxy of 1 to 4 carbon atoms, arylalkoxy, halo, amino; which comprises treating a compound of the formula: wherein Ri and R2 are as defined above, with an acid catalyst. The present invention is also directed to the compounds of the formula VI, as well as to processes for their preparation. The term "acid catalyst" represents a Lewis acid or a Bronsted acid. Representative Lewis acids are zinc chloride, zinc iodide, aluminum chloride, and aluminum bromide. Representative Bronsted acids include: inorganic acids, such as sulfuric and phosphoric acids; carboxylic acids, such as acetic and trifluoroacetic acids; sulphonic acids, such as methanesulfonic, benzenesulfonic, 1-naphthalenesulfonic, 1-butanesulfonic, ethanesulfonic, 4-ethylbenzenesulfonic, 1-hexansulfonic, 1,5-naphthalenedisulfonic, 1-octanesulfonic, camphorsulfonic, trifluoromethanesulfonic, and p-toluenesulfonic; and polymeric arylsulfonic acids, such as Nafion®, Amberlyst® or A berlite®. Preferred acids to be used to catalyze the processes of the present invention are the sulphonic 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 formula above, the term "C 1 -C 4 alkoxy" represents groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, and similar groups. The term "halo" refers to fluorine, chlorine, bromine, or iodine groups. The term "alkyl of 1 to 6 carbon atoms" represents a straight or branched chain alkyl chain having from one to six carbon atoms. Typical alkyl groups 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 similar. The term "alkyl of 1 to 4 carbon atoms" represents a straight or branched chain alkyl chain having from one to four carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl , i-butyl, and t-butyl. The term "aryl" represents groups such as phenyl and substituted phenyl. The term "substituted phenyl" represents a phenyl group substituted with one or more portions 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 the groups 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- methyl-phenyl, 2,4,6-trifluorophenyl, 2-trifluoromethylphenyl, 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 "arylalkyl" represents an alkyl group of 1 to 4 carbon atoms carrying one or more aryl groups. Representative of these groups include benzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl (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-dichloro-phenyl) 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 group of 1 to 4 carbon atoms carrying one or more aryl groups. Representative of this group include benzyloxy, 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, β-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 group of 2 to 10 carbon atoms, alkenyl of 4 to 10 carbon atoms, or aryl (alkyl of 1 to 10 carbon atoms) thermally labile or acid-labile" represents a group that is easily removed from the group sulfoxide (SO) by heating, or by treatment with the acid catalyst. Alkyl groups of 2 to 10 thermally labile or acid-labile carbon atoms are straight or branched chain alkyl chains having from two to ten carbon atoms, and having at least one beta hydrogen atom. Alkyl groups of 2 to 10 thermally labile carbon atoms or representative acid labile include ethyl, n-propyl, i-propyl, 1,1-dimethylpropyl, n-butyl, sec-butyl, t-butyl, 1,1 -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. Alkenyl groups of 4 to 10 thermally labile or acid-labile carbon atoms are straight or branched chain alkenyl chains having from four to ten carbon atoms, at least one unsaturation site, and any one of a beta or hydrogen atom. a hydrogen atom delta. Representative heat-labile or acid-labile carbon 4 to 10 carbon atoms 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 similar. The term thermally labile or acid-labile aryl (C1-C10 alkyl) represents alkyl groups of 2 to 10 thermally labile or acid-labile carbon atoms additionally containing one or more aryl groups and aryl groups substituted with methyl. Representative aryl groups (alkyl of 1 to 10 carbon atoms) include benzyl, diphenylmethyl, triphenylmethyl, p-methoxybenzyl, 2-phenylethyl, 2-phenyl-propyl, 3-phenylpropyl, and the like. The starting compounds for the compounds and processes of the present invention can be prepared by a number of routes. A method for preparing the compounds of formula II is shown in Scheme 1. Scheme 1 In general, a compound of formula VII is converted to a styryl sulfide by reaction with a mercaptan of the formula HSR3 in the presence of a Lewis acid. The compound of formula VIII is oxidized to a styryl sulfoxide, a compound of formula II. More specifically, a compound of formula VII, wherein R. and R.sup.2 are as defined above, are treated with a Lewis acid, such as titanium (IV) chloride. This reaction is carried out in an anhydrous organic solvent, such as dry tetrahydrofuran, at a temperature of about 0 ° C 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 group of 1 to 10 carbon atoms, alkenyl of 4 to 10 carbon atoms, or aryl (alkyl of 1 to 10 carbon atoms) thermally labile or acid-labile. Preferably, the mercaptan and the amine base are added as a solution in the reaction solvent. A representative amine base is triethylamine. After the addition of the mercaptan and the amine base, the reaction is usually heated to a temperature of about 35 ° C to about 65 ° C, preferably to about 50 ° C. The products of this reaction can be purified using techniques well known in the chemical art, such as crystallization or chromatography. The compound of formula VIII, wherein Rx and R2 are as defined above, and R3 is an alkyl group of 2 to 10 carbon atoms, alkenyl of 4 to 10 carbon atoms, aryl (alkyl of 1 to 10 carbon atoms) ) thermally labile or acid-labile, then oxidized to produce the compounds of formula II. Oxidizing agents suitable for this reaction are peracids, such as peracetic acid and m-chloroperoxybenzoic acid, and hydrogen peroxide. This oxidation reaction typically runs in an organic solvent, such as toluene, methylene chloride, chloroform, or carbon tetrachloride. When a peracid is used as the oxidant, the reaction is usually carried out at a temperature of about -30 ° C 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 regioisomer of the compounds of formula II can be prepared selectively by a second route, shown in Scheme 2. Scheme 2 Generally, a benzyl alcohol, a compound of formula IX, is reacted with a mercaptan of the formula R3SH to produce a benzyl sulfide, a compound of formula X. This benzyl sulfide is reacted with a strong base, forming a benzyl 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 styryl sulfide, a compound of formula VIIIZ. This styryl sulfide is then oxidized with an oxidizing agent, to produce the compound of formula IIZ. The first step in the synthesis of Z-styryl sulfoxide compounds is the conversion of a benzyl alcohol to a benzyl sulfide, the compound of formula X. The reaction of the compound of formula IX, wherein R2 is as defined above, with a mercaptan of the formula R3SH, wherein R3 is an alkyl group of 2 to 10 carbon atoms, alkenyl of 4 to 10 carbon atoms, or aryl (alkyl of 1 to 10 carbon atoms) thermally labile or acid labile having a tertiary carbon atom adjacent to the sulfur atom, in the presence of a Lewis acid, produces the benzyl sulfide, a compound of formula X. The Lewis acids suitable for this transformation are zinc bromide, zinc chloride, zinc iodide, ferric chloride, titanium (IV) chloride, aluminum trichloride, and aluminum tribromide, preferably zinc iodide. 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, the reaction is complete after about 18 hours. The benzyl sulfide 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 alkyl lithiums, such as n-butyl lithium, t-butyl lithium, sec-butyl lithium, and methyl lithium. The preferred strong base for this reaction is n-butyllithium. The preferred solvent for this reaction is dry tetrahydrofuran. When n-butyllithium is used as the strong base, the reaction is carried out at a temperature of about -35 ° C to about -15 ° C. The benzylic anion is condensed are a benzaldehyde to prepare an intermediate condensation product. The benzaldehyde has the general formula p-Ri (C6H4) CHO, where Ri is hydrogen, alkoxy of 1 to 4 carbon atoms, arylalkoxy, halo, or amino. Preferably, the benzylic anion is prepared and the condensation product is formed in itself 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. Preferably, the methanesulfonyl chloride is added to the reaction mixture shortly after the formation of the condensation product. This intermediate compound is reacted with a strong second phase to produce a styryl sulfide, a compound of formula VIIIZ wherein Ri, R2 and R3 are as defined above. 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; alkyl lithiums, such as n-butyl lithium, t-butyl lithium, sec-butyl lithium, and methyl lithium; and metal amides, such as sodium amide, magnesium diisopropylamide, and lithium diisopropylamide. The preferred strong base for this reaction is potassium t-butoxide. Typically, this reaction is carried out at about 15 ° C at about room temperature, preferably at room temperature. The styryl sulfide is oxidized to prepare the corresponding styryl superoxide. 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 methylene chloride. This oxidation can be carried out at a temperature at -40 ° C to about 0 ° C. Alternatively, when R3 has a tertiary carbon adjacent to the sulfur atom, the benzyl sulfide intermediate (compound of formula X) can be used to produce a mixture of the E and Z isomers of the styryl sulfoxides, the compounds of formula II . This synthesis is represented in Scheme 3. Scheme 3 The benzyl sulfide, prepared as described above, is oxidized to produce the corresponding benzyl sulfoxide. 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 compound is reacted with a strong second base to produce the styryl sulfoxide. The benzyl sulfide, the compound of formula X, wherein R2 is as defined above, and R3 is an alkyl group of 2 to 10 carbon atoms, alkenyl of 4 to 10 carbon atoms, or aryl (alkyl of 1 to 10 carbon atoms) thermally labile or acid labile having a tertiary carbon atom adjacent to the sulfur atom, is oxidized to produce the corresponding benzyl sulfoxide, the compound 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 ° C to about 5 ° C. The benzyl sulfoxide, the compound 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 metal alkoxides, such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithium t-butoxide, and potassium t-butoxide; sodium hydride; alkyl lithiums, such as n-butyl lithium, t-butyl lithium, sec-butyl lithium, and methyl lithium; and metal amides, such as sodium amide, magnesium diisopropylamide, and lithium diisopropylamide. The preferred base for this transformation is n-butyl lithium. This deprotonation reaction is carried out in a dry organic solvent, such as tetrahydrofuran or 1,2-dimethoxyethane, at a temperature of about -25 ° C. The benzylic anion is condensed, without isolation, with a benzaldehyde compound of the formula p-Ri (C6H4) CHO, where Ra is as defined above. Preferably, about one equivalent of the benzaldehyde is added to the cold solution prepared as described in the preceding 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 an 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. The acid chloride is added to the cold reaction mixture, then the resulting mixture is allowed to warm to room temperature. Preferably, the methanesulfonyl chloride is added to the reaction mixture shortly after the formation of the condensation product, which eliminates the need to add additional base. The resulting intermediate compound is reacted with a strong second base to produce the E and Z styryl sulfoxides, compounds of formula II wherein Ri, R2, and R3 are as defined above. The second representative strong bases for this elimination reaction include metal alkoxides, such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithium t-butoxide, and potassium t-butoxide.; sodium hydride; alkyl lithiums, such as n-butyl lithium, t-butyl lithium, sec-butyl lithium and methyl lithium; 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%, such as 1.2 equivalents, of the second base is added. Generally, this reaction is carried out at a temperature of about 15 ° C at about room temperature, preferably at room temperature.

The styryl sulfoxides are useful for the preparation of a benzothiophene styryl sulfide as shown in Scheme 4. Scheme 4 These benzothiophene styryl sulfides, wherein Ri and R2 are as defined above, are prepared from the styryl sulfoxides. Typically, a solution of styryl sulfoxide, wherein Ri and R2 are as defined above, and R3 is an alkyl group of 1 to 10 carbon atoms, alkynyl of 4 to 10 carbon atoms, or aryl (alkyl) 1 to 10 carbon atoms) thermally labile or acid-labile, is added to a solution of an acid catalyst at a temperature of about 100 ° C to about 140 ° C, wherein the acid catalyst is defined above. The concentration of acid catalyst is dependent 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 is in a final concentration of about 0.2 M and added for 6 hours, the acid concentration is about 0.002 M. When the styryl sulfoxide is in a final concentration of about 0.05 M and added for 30 minutes, the acid concentration is about 0.025 M. Significant amounts of the compounds of formula VI are present in the reaction after about one to two hours. Longer reaction times give rise to the production of the compounds of formula I. These compounds of formula VI can be subsequently converted to the compounds of formula I by treatment with additional acid, such as from about 0.5 to about 3 equivalents, and heating to about 100 ° C 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 both, the formation of the compounds of formula VI and their conversion to 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-2-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 the methods for their preparation from the compounds of formula I. An improved synthesis of a group of these 3-aroyl-2-arylbenzo [b] -thiophenes from the compounds of formula I, wherein Rx and R2 are hydrogen, alkoxy of 1 to 4 carbon atoms, or arylalkoxy, is represented in Scheme 5. Scheme 5 The compound of formula I, wherein R_ and R2 are hydrogen, alkoxy of 1 to 4 carbon atoms, or arylalkoxy, is acylated with the compound of formula XII, wherein R is chloro or hydroxy, in the presence of boron trichloride 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-trichloropropane, 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 ° C to about 25 ° C, preferably at 0 ° C. The reaction is best carried out at a concentration of the benzothiophene compound of formula I from about 0.2 M to about 1.0 M. The acylation reaction is usually complete after about two hours to about eight hours. When Rx and / or R2 is an alkoxy group of 1 to 4 carbon atoms or arylalkoxy, the acylated benzothiophene is preferably converted to a compound of formula XIII, wherein R5 and / or R6 are hydroxy, without isolation of the reaction product. Acylation This conversion is carried out by adding additional boron trichloride or additional boron tribromide, and heating the reaction mixture. Preferably, two to five molar equivalents of boron trichloride are added to the reaction mixture, more preferably three molar equivalents. This reaction is carried out at a temperature of about 25 ° C to about 40 ° C, preferably at 35 ° C. The reaction is usually complete after about 4 hours to about 48 hours. The acylation reaction or the acylation / dealkylation reaction is quenched with an alcohol or a mixture of alcohols. Suitable alcohols for use in quenching the reaction include methanol, ethanol, and isopropanol. Preferably, the acylation / dealkylation reaction mixture is added to a 95: 5 mixture of ethanol and methanol (3A ethanol). The ethanol 3A can be at room temperature, or heated to reflux, preferably at reflux. When quenching is done in this manner, the compound of formula XIII conveniently crystallizes from the resulting alcohol mixture. Generally, 1.25 ml to 3.75 ml of alcohol are used per millimole of the benzothiophene raw material. The following examples further illustrate the present invention. The examples are not intended to be limiting to the scope of the invention in any respect, and should not be construed in this way. All experiments were run under positive pressure of dry nitrogen. All solvents and reagents will be used as obtained. The percentages are usually calculated on a weight basis (w / w); except for high-resolution liquid chromatography (HPLC) solvents, which was calculated on a volume (v / v) basis. The proton nuclear magnetic resonance spectra (H NMR) and the 13C nuclear magnetic resonance spectra (13 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 a GE QE-300 spectrometer at 300.15 MHz. Flash chromatography on silica gel was performed 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 an Elemental Analyzer of Control Equipment Corporation 440. Elemental analyzes for sulfur were determined on a Brinkman Colorimetric Elemental Analyzer. The melting points were determined in open glass capillaries in an apparatus for Mel-Temp II melting point and are not corrected. The field desorption mass spectrum (FDMS) were obtained using a Varian Instruments mass spectrometer VG 70-SE or VG ZAB-3F. The mass spectra by bombardment of high resolution free atoms (FABMS) were obtained using a Varian Instruments VG ZAB-2SE mass spectrometer. The in-yields of 6-methoxy-2- (4-methoxy-phenyl) benzo [b] thiophene were determined by high-performance liquid chromatography (HPLC) as compared to an authentic sample of this compound prepared by the synthetic routes published See U.S. Patent No. 4,133,814. Typically, the samples of the reaction mixture were diluted with acetonitrile, and the diluted sample was assayed 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 System Gradient Time (minutes) A (%) B (%) 0 50 50 2 50 50 20 20 80 35 20 80 37 50 50 45 50 50 A: 0.01 M aqueous sodium phosphate (pH 2.0) B: Acetonitrile The amount (percentages) of 6-hydroxy-2- (4-hydroxy-phenyl) -3- [4- (2-piperidinoethoxy) benzoyl] -benzo [b] thiophene hydrochloride in the crystalline material (potency) was determined by the next 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 75 mM potassium phosphate buffer (pH 2.0) and acetonitrile. An aliquot of this solution (10 μl) was assayed by high performance liquid chromatography, using a Zorbax Rx-C8 column (25 cm x 4.6 mm ID, particle size 5 μm) and UV detection (280 nm). The following solvent system gradient was used: Solvent System Gradient (Power) Time (minutes) A (%) B (%) 0 70 30 12 70 30 14 25 75 16 70 30 25 70 30 A: 75 mM KH2P04 buffer solution (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 maximum area, the slope (m ), and the intercept (b) of the calibration curve with the following equation:% power = maximum area -bx sample volume (mi) m sample weight (mg) The amount (percentage) 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 dimethylsulfoxide. A sample of this solution was analyzed in a gas chromatograph, using a DB Wax column (30 m x 0.53 mm ID, 1 μm particle), with a column flow of 10 ml / minute and detection by flame ionization. The temperature of the column was heated from 35 ° C to 230 ° C for a period of 12 minutes. The amount of solvent was determined by comparison to the internal standard (2-butanol). Example 1 Et-Butyl 4,4'-dimethoxystylbenyl sulfoxide A. Preparation of Et-Butyl 4,4'-dimethoxystilbenyl Sulfide A solution of deoxyisoisole (12.82 g) in tetrahydrofuran (100 ml) was treated with titanium (IV) chloride (10.43 g). During the dropwise addition of the titanium (IV) chloride, the reaction mixture was cooled to maintain the temperature below 35 ° C. When the addition was complete, the resulting mixture was stirred at 30 ° C. After an additional 30 minutes, this mixture was treated with a solution of 2-methyl-2-propanothiol (6.76 ml) and triethylamine (16.70 ml) in tetrahydrofuran (15 ml). The resulting mixture was stirred at 50 ° C. Two hours later, the mixture was added to ten percent sodium carbonate (500 ml). The resulting mixture was extracted with methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to give 17.2 g of an oil, which crystallized by cooling to room temperature. This crystalline material was recrystallized from hot ethanol to give 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-t-butyl 4,4'-dimethoxystilyl sulfoxide The crystalline compound prepared as 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 ten minutes. The resulting mixture was extracted with saturated sodium sulfite and saturated saline. The organic phase was concentrated in vacuo. The residue was recrystallized from ethyl acetate / heptane to give 14.11 g of the title compound. Melting point 104 ° C (decomposition). Analysis calculated for C20H24O3S: C, 69.74; H, 7.02; S, 9.31. Found: C, 69.47; H, 7.04; S, 9.54. EXAMPLE 2 Zt-Butyl 4,4'-dimethoxystilyl sulfoxide A. Preparation of t-butyl 4,4'-methoxybenzyl sulfide 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 one portion. The resulting mixture was stirred at room temperature. After about 18 hours, the reaction was diluted with water (100 ml) and methylene chloride (100 ml). The organic phase was extracted, dried over magnesium sulfate, filtered and concentrated in vacuo to give 14.4 g of an oil. 2 H NMR (CDC13): d 7.28 (d, 2 H), 6.85 (d, 2 H), 3.77 (s, 3 H), 3.73 (s, 2 H), 1.36 (s, 9 H). 13 C NMR (CDCl 3): d 130, 114, 56, 35, 32. Analysis calculated for CX2HX8OS: C, 68.52; H, 8.63. Found: C, 68.80; H, 8.67. B. Preparation of Z-t-butyl 4,4'-dimethoxystilbenyl sulfide A solution of the compound prepared as described in Example 2A (2.51 g) in tetrahydrofuran (50 ml) was cooled to about -20 ° C. This cold solution was treated with a solution of n-butyllithium in hexane (1.6 M, 7.47 ml) for ten minutes. The resulting solution was allowed to warm to about 0 ° C for 35 minutes. This cold solution was treated with p-anisaldehyde (1.46 ml). After an additional 15 minutes, the reaction solution was treated with methanesulfonyl chloride (0.95 ml). The resulting reaction was allowed to warm to 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 quenched by the reaction of 1 N hydrochloric acid (12.0 ml). The organic phase was separated, dried over magnesium sulfate, filtered, and concentrated to give an oil (4.4 g). XH NMR (CDC13): d 7.95 (d, 2 H), 7.05 (s, 1 H), 6.9 (d, 1 H), 6.8 (dd, 2 H), 3.75 (s, 3 H), 0.95 ( s, 9 H). 13 C NMR (CDCl 3): d 153, 139, 114, 56, 32. C. Preparation of Zt-butyl 4,4'-dimethoxystilyl sulfoxide The compound of Example 2B was converted to the title compound using the procedures substantially as described in the IB example. XH NMR (CDCl 3): d 7.61 (d, 1 H), 7.56 (d, 1 H), 7.1 (s, 1 H), 6.9 (dd, 2 H), 3.83 (s, 3 H), 1.05 ( s, 9 H). 13 C NMR (CDCl 3): d 142, 132.5, 131, 118, 117, 56, 24. Analysis calculated for C 20 H 24 O 3 S: C, 69.74; H, 7.02. Found: C, 69.98; H, 6.94. Example 3 E and Zt-butyl 4,4'-dimethoxystilyl sulfoxide A. Preparation of t-butyl 4-methoxybenzyl sulfide 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-propantiol (9.92 ml) in one portion. The resulting mixture was stirred at room temperature. After about 18 hours, the reaction was diluted with water (100 ml) and methylene chloride 100 ml). The organic phase was extracted, dried over magnesium sulfate, filtered and concentrated in vacuo to give 14.4 g of an oil. X H NMR (CDCl 3): d 7.28 (d, 2 H), 6.85 (d, 2 H), 3.77 (s, 3 H), 3.73 (s, 2 H), 1.36 (s, 9 H). 13 C NMR (CDCl 3): d 130, 114, 56, 35, 32. Analysis calculated for CX 2 H 8 8 OS: C, 68.52; H, 8.63. Found: C, 68.80; H, 8.67. B. Preparation of t-Butyl 4-methoxybenzyl sulfoxide A solution of the compound prepared as 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) for 30 minutes. With the complete addition of peracetic acid, the reaction was treated with saturated saline solution and sodium bicarbonate. The organic phase was extracted, dried over magnesium sulfate, filtered and concentrated to give a yellow precipitate. This residue was treated with hexane (100 ml), and the resulting mixture was stirred at room temperature. After about 18 hours, the mixture was filtered and the solid was washed with hexane (100 ml). The solid material was dried in vacuo to give 14.07 g of the title compounds. Melting point 124-126 ° C. NMR of H (CDC13): d 7.26 (d, 2 H), 6.89 (d, 2 H), 3.79 (d, 1 H), 3.78 (s, 3 H), 3.58 (d, 1 H), 1.3 ( s, 9 H). 13 C NMR (CDCl 3): d 132, 114, 56, 53, 23. Analysis calculated for CX2HX802S: C, 63.68; H, 8.02. Found: C, 63.72; H, 7.93. C. Preparation of E and Zt-Butyl 4,4'-dimethoxystilyl sulfoxide A solution of the compound prepared as described in Example 3B (10.0 g) in tetrahydrofuran (140 ml) was cooled to about -30 ° C to -25 ° C. ° 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 dry ice / acetone bath was removed and the reaction was allowed to warm to about 20 ° C. This mixture was treated with methanesulfonyl chloride (3.5 ml). The temperature of the reaction rose from about 20 ° C to about 35 ° C with the addition of 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 was treated with 1N hydrochloric acid (51.0 ml). The phases were separated, and the organic layer was dried over magnesium sulfate, filtered and concentrated to give an oil (16.67 g). This material was used in the next step without further purification. The carbon and proton NMR spectra were similar to those obtained for the compound prepared as described in Examples 1 and 2. Example 4 E and Z-3- (4,4'-dimethoxystylbenyl sulfide) -6-methoxy- 2- (4-methoxyphenyl) benzo [b] thiophene A solution of p-toluenesulfonic acid monohydrate (552 mg) in toluene (111 ml) was heated to reflux, and water was removed allowing it to be collected in a Dean trap -Stark. A solution of the compound prepared as described in Example 1 (10 g) in toluene (34 ml) was added to the acid solution at reflux for six hours. After an additional two hours, the 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 separated, dried over sodium sulfate, filtered, and concentrated in vacuo to give 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 to give an oil. This oil was treated with diethyl ether to selectively crystallize the regioisomer that eluted initially (155 mg). The mother liquor of these crystallizations was enriched in the regioisomer that eluted later. Isomer that initially eluted lE NMR (CDC13): d 7.71 (d, 2 H), 7.64 (d, 1 H), 7.46 (d, 2 H), 7.06 (d, 1 H), 6.94 (d, 2 H) ), 6.92 (d, 2 H), 6.90 (m, 1 H), 6.85 (d, 2 H), 6.59 (s, 1 H), 6.45 (d, 2 H), 3.86 (s, 3 H), 3.85 (s, 3 H), 3.80 (s, 3 H), 3.66 (s, 3 H). High resolution FABMS calculated for C32H2904S2 (MHp 541, 1507. Found: 541, 1491.

Isomer eluting after XH NMR (CDCl 3): d 7.90 (d, 1 H), 7.62 (d, 2 H), 7.24 (1 H), 7.08 (d, 2 H), 7.02 (dd, 1 H), 6.96 (d, 2 H), 6.74-6.71 (d, 2 H), 6.70 (d, 2 H), 6.55 (d, 2 H), 6.21 (s, 1 H), 3.86 (s, 3 H), 3.85 (s, 3 H), 3.76 (s) , 3 H), 3.67 (s, 3 H). FDMS: m / z = 540 (mp Example 5 6-Methoxy-2- (4-methoxyphenyl) enzo [b] thiophene The compound (isomer that eluted initially) prepared as described in Example 4 (125 mg) was added to a reflux solution of p-toluenesulfonic acid monohydrate (4.2 mg) in toluene (1.5 ml) After six hours, methanesulfonic acid (7.5 μl) was added to the reaction mixture. The reaction was allowed to cool to room temperature The resulting mixture was diluted with acetonitrile and tested by HPLC, showing an in situ yield of 71.1% of the title compound.

Example 6 1,2-dichloroethane solvate of 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) -benzoyl) benzo [b] thiophene hydrochloride A. Preparation of 4- (2 ethylpiperidinoethoxy) 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 at 80 ° C. After one hour, the mixture was cooled to about 55 ° C, and treated with additional 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 1- (2-chloroethyl) piperidine hydrochloride were added until the starting 4-hydroxybenzoate ester was consumed. When the reaction was complete, the reaction mixture was treated with water (60 ml) and allowed to cool to room temperature. The aqueous layer was discarded, and the organic layer was concentrated in vacuo at 40 ° C and 0.544 kg / cm (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 as described in Example 6A (about 13.87 g) in methanol (30 ml) was treated with 5 N sodium hydroxide (15 ml). ), and warmed to 40 ° C. After 4-1 / 2 hours, water (40 ml) was added. The resulting mixture was cooled to 5-10 ° C, and concentrated hydrochloric acid (18 ml) was slowly added. The title compound crystallized during acidification. This crystalline product was collected by filtration, and dried in vacuo at 40-50 ° C to give 83% yield of the title compound. Melting point 270-271 ° C. C. Preparation of 4- (2-piperidinoethoxy) enzoyl chloride hydrochloride A solution of the compound prepared as described in Example 6B (30.01 g) and dimethylformamide (2 ml) in methylene chloride (500 ml) was treated with chloride oxalyl (10.5 mi) during a period of 30-35 minutes. After stirring for about 18 hours, the reaction was assayed for completion by HPLC analysis. Additional oxalyl chloride may be added to the reaction if the starting carboxylic acid is present. When the reaction was complete, 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 give the title compound as a solid. D. Preparation of the 1,2-dichloroethane solvate of 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) benzoyl] benzo [b] thiophene hydrochloride A mixture of the compound prepared as described in Example 5 (2.92 g), the compound prepared as described in Example 6C (3.45 g), and 1,2-dichloroethane (52 ml) was cooled to about 0 ° C. Gas boron trichloride was condensed in a cold graduated cylinder (2.8 ml), and added to the cold mixture described above. After eight hours at 0 ° C, the reaction mixture was treated with additional boron trifluoride (2.8 ml). The resulting solution was heated to 35 ° C. After 16 hours the reaction was complete. Methanol (30 mL) was treated with the reaction mixture above, over a period of 20 minutes, causing the methanol to heat to reflux. The resulting paste was stirred at 25 ° C. After one hour, the crystalline product was filtered, washed with cold methanol (8 ml), and dried at 40 ° C in vacuo to give 5.14 g of the title compound. Melting point 225 ° C. Power (HPLC): 86.8% 1,2-Dichloroethane (gas chromatography): 6.5%.

It is noted that in relation to this date, the best known method for the applicant to carry out the aforementioned invention, 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 (17)

1. CLAIMS 1. A compound of the formula: vi characterized in that: R x is hydrogen, alkoxy of 1 to 4 carbon atoms, arylalkoxy, halo, or amino; and R2 is hydrogen, alkoxy of 1 to 4 carbon atoms, arylalkoxy, halo, or amino 2. The compound according to claim 1, characterized in that: Rx is hydrogen, alkoxy of 1 to 4 carbon atoms, or arylalkoxy; and R2 is hydrogen, alkoxy of 1 to 4 carbon atoms, or arylalkoxy. 3. The compound according to claim 2, characterized in that: Rx is hydrogen or alkoxy of 1 to 4 carbon atoms; R2 is hydrogen or alkoxy of 1 to 4 carbon atoms. 4. The compound according to claim 3, characterized in that Rx and R2 are alkoxy of 1 to 4 carbon atoms. 5. The compound according to claim 4, characterized in that Rx and R2 are methoxy. 6. A process for preparing a compound of the formula: wherein: R x is hydrogen, alkoxy of 1 to 4 carbon atoms, arylalkoxy, halo, or amino; and R2 is hydrogen, alkoxy of 1 to 4 carbon atoms, arylalkoxy, halo, or amino; the process is characterized in that it comprises reacting a compound of the formula: wherein: Ri and R2 are as defined above, and R3 is an alkyl group of 2 to 10 carbon atoms, alkenyl of 4 to 10 carbon atoms, or aryl (alkyl of 1 to 10 carbon atoms) thermally labile or acid-labile, with an acid catalyst at a temperature of about 100 ° C to about 140 ° C, where the concentration of the compound of formula II is from about 0.05 M to about 0.
2. 2 M. 7. The process of according to claim 6, characterized in that: Rx is hydrogen, alkoxy of 1 to 4 carbon atoms, or arylalkoxy; and R2 is hydrogen, alkoxy of 1 to 4 carbon atoms, or arylalkoxy. 8. The process according to claim 7, characterized in that the acid catalyst is selected from the group consisting of methanesulfonic acid, benzenesulfonic acid, 1-naphthalenesulfonic acid, 1-butanesulfonic acid, ethanesulfonic acid, 4-ethylbenzenesulfonic acid, 1- hexansulfonic acid, 1,5-naphthalenedisulfonic acid, 1-octansulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid, Nafion, Amberlyst or Amberlite. 9. The process according to claim 8, characterized in that the acid catalyst is selected from the group consisting of methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, Nafion®, Amberlyst® and Amberlite®. The process according to claim 9, characterized in that the acid catalyst is selected from the group consisting of methanesulfonic acid, p-toluenesulfonic acid, Nafion®, Amberlyst® and Amberlite®. The process according to claim 10, characterized in that R3 is an alkyl group of 2 to 10 carbon atoms or aryl (alkyl of 1 to 10 carbon atoms) thermally labile or labile to acid. 12. The process according to claim 11, characterized in that R3 is an alkyl group of 2 to 10 carbon atoms thermally labile or acid-labile. 13. The process according to claim 12, characterized in that R3 is t-butyl. 14. The process according to claim 13, characterized in that Rx and R2 are alkoxy of 1 to 4 carbon atoms. 15. The process according to claim 14, characterized in that Rx and R2 are methoxy. 16. The process according to claim 15, characterized in that the acid catalyst is p-toluenesulfonic acid. 17. A process for preparing a compound of the formula: wherein: R x is hydrogen, alkoxy of 1 to 4 carbon atoms, arylalkoxy, halo, amino; and R2 is hydrogen, alkoxy of 1 to 4 carbon atoms, arylalkoxy, halo, amino; the process is characterized in that it comprises treating a compound of the formula: wherein Rx and R2 are as defined above, with an acid catalyst.