EA000606B1 - Vinyl sulfenic acid derivatives and process for their synthesis - Google Patents

Abstract

1. A compound of the formula wherein: R1 is hydrogen, C1-C4 alkoxy, arylalkoxy, halo, or amino; R2 is hydrogen, C1-C4 alkoxy, arylalkoxy, halo, or amino; R4 is OSi(R)3, NR5R6, or SR8; each R is independently C1-C6 alkyl, aryl, or arylalkyl; R5 and R6 are independently hydrogen, C1-C6 alkyl, arylalkyl, or aryl; or R5 and R6 together with the nitrogen atom form a ring selected from piperidine, pyrrolidine, morpholine, or hexamethylimine; and R8 is C1-C6 alkyl, aryl, or arylalkyl. 2. The compound of Claim 1 wherein: R1 is hydrogen, C1-C4 alkoxy, or arylalkoxy; and R2 is hydrogen, C1-C4 alkoxy, or arylalkoxy. 3. The compound of Claim 2 wherein: R4 is OSi(R)3; and each R is independently C1-C6 alkyl, aryl, or arylalkyl. 4. The compound of Claim 3 wherein R4 is OTMS, OTES, OTIPS, ODMIPS, ODEIPS, OTDS, OTBDMS, OTBDPS, OTBS, OTPS, ODPMS or OTBMPS. 5. The compound of Claim 4 wherein R4 is OTMS, OTES, ODMIPS, ODEIPS, OTBDMS, OTBS or OTPS. 6. The compound, of Claim 5 wherein R1 and R2 are C1-C4 alkoxy. 7. The compound of Claim 6 wherein R1 and R2 are methoxy and R4 is OTMS. 8. The compound of Claim 2 wherein: R4 is NR5R6; and R5 and R6 are independently hydrogen, C1-C6 alkyl, arylalkyl, or aryl; or R5 and R6 together with the nitrogen atom form a ring selected from piperidine, pyrrolidine, morpholine, and hexamethylimine. 9. The compound of Claim 8 wherein R5 and R6 are independently hydrogen, C1-C6 alkyl, or arylalkyl; or R5 and R6 together with the nitrogen atom form a ring selected from piperidine and pyrrolidine. 10. The compound of Claim 9 wherein R1 and R2 are C1-C4 alkoxy. 11. The compound of Claim 10 wherein R1 and R2 are methoxy, and R5 and R6 are methyl. 12. The compound of Claim 10 wherein R1 and R2 are methoxy, R5 is hydrogen, and R6 is benzyl. 13. The compound of Claim 2 wherein: R4 is SR8; and R8 is C1-C6 alkyl, aryl, or arylalkyl. 14. The compound of Claim 13 wherein R8 is C1-C6 alkyl or arylalkyl. 15. The compound of Claim 14 wherein R8 is C1-C6 alkyl. 16. The compound of Claim 15 wherein R1 and R2 are C1-C4 alkoxy. 17. The compound of Claim 16 wherein R1 and R2 are methoxy, and R8 is ethyl. 18. A process for preparing a compound of the formula III wherein: R1 is hydrogen, C1-C4 alkoxy, arylalkoxy, halo or amino; R2 is hydrogen, C1-C4 alkoxy, arylalkoxy, halo or amino; R4 is OSi(R)3, NR5R6 or SR8; each R is independently C1-C6 alkyl, aryl or arylalkyl; R5 and R6 are independently hydrogen, C1-C6 alkyl, arylalkyl or aryl; or R5 and R6 together with the nitrogen atom form a ring selected from piperidine, pyrroimidine, morpholine, or hexamethylimine; and R8 is C1-C6 alkyl, aryl or arylalkyl; which comprises: (1) reacting a compound of the formula II wherein: R1 and R2 are as defined above, and R3 is a thermally-labile or acid-labile C2-C10 alkyl, C4-C10 alkenyl or ary (C1-C10) alkyl group; with a silylating reagent to produce a sulfenate silyl ester of the formula IV wherein: R1 and R2 are as defined above; R7 is OSi(R)3; and each R is independently C1-C6 alkyl, aryl or arylalkyl; (2) optionally reacting said sulfenate silyl ester with an amine of the formula HNR5R6 wherein R5 and R6 are as defined above; or (3) optionally reacting said sulfenate silyl ester with a mercaptan of the formula HSR8, wherein R8 is as defined above, in the presence of an amine base. 19. The process of Claim 1 for preparing a compound of the formula IV wherein: R1 is hydrogen, C1-C4 alkoxy, arylalkoxy, halo, or amino; R2 is hydrogen, C1-C4 alkoxy, arylalkoxy, halo, or amino; R7 is OSi(R)3; and each R is independently C1-C6 alkyl, aryl, or arylalkyl; which comprises reacting a compound of the formula wherein: R1 and R2 are as defined above and R3 is a thermally-labile or acid-labile C2-C10 alkyl, C4-C10 alkenyl, or aryl(C1-C10)alkyl group; with a silylating reagent. 20. The process of Claim 19 wherein: R1 is hydrogen, C1-C4 alkoxy or arylalkoxy; and R2 is hydrogen, C1-C4 alkoxy or arylalkoxy. 21. The process of Claim 20 wherein: R7 is OTMS, OTES, OTIPS, ODMIPS, ODEIPS, OTDS, OTBDMS, OTBDPS, OTBS, OTPS, ODPMS or OTBMPS. 22. The process of Claim 21 wherein the silylating reagent is a bis(trialkylsilyl)urea or a combination of a hexaalkyl-disilylzane and a catalytic amount of a chlorotrialkylsilane, and R is C1-C6 alkyl. 23. The process of Claim 22 wherein the silylating reagent is bis(trimethylsilyl)urea and R is methyl. 24. The process of Claim 23 wherein R3 is a thermally-labile or acid-labile C2-C10 alkyl group. 25 The process of Claim 24 wherein R1 and R2 are raethoxy, and R3 is t-butyl. 26. The process of Claim 18 for preparing a compound of the formula wherein: R1 is hydrogen, C1-C4 alkoxy, arylalkoxy, halo, amino; R2 is hydrogen, C1-C4 alkoxy, arylalkoxy, halo, amino; and R5 and R6 are independently hydrogen, C1-C6 alkyl or aryl, or R5 and R6 together with the nitrogen atom form a ring selected from 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 a thermally-labile or acid-labile C2-C10 alkyl, C4-C10 alkenyl, or aryl(C1-C10 alkyl) group; with a silylating reagent to produce a sulfenate silyl ester of the formula wherein: R1 and R2 are as defined above; R7 is OSi(R)3; and each R is independently C1-C6 alkyl, aryl or arylalkyl; and (2) reacting said sulfenate silyl ester with an amine of the formula HNR5R6 wherein R<5> and R6 are as defined above. 27. The process of Claim 26 wherein: R1 is hydrogen, C1-C4 alkoxy or arylalkoxy; and R2 is hydrogen, C1-C4 alkoxy or arylalkoxy. 28. The process of Claim 27 wherein the silylating reagent is bis(trimethylsilyl)urea and R is methyl. 29. The process of Claim 28 wherein R3 is a thermally-labile or acid-labile C2-C10 alkyl group. 30. The process of Claim 29 wherein R1 and R2 are methoxy, and R3 is t-butyl. 31. The process of Claim 30 wherein R5 and R6 are independently hydrogen, C1-C6 alkyl or aryl. 32. The process of Claim 31 wherein R5 and R6 are methyl, or R5 is hydrogen and R6 is benzyl. 33. The process of Claim 18 for preparing a compound of the formula wherein: R1 is hydrogen, C1-C4 alkoxy, arylalkoxy, halo, amino; R2 is hydrogen, C1-C4 alkoxy, arylalkoxy, halo, amino; and R8 is C1-C6 alkyl, aryl, or arylalkyl comprising the steps of (1) :reacting a compound of the formula II wherein: R1 and R2 are as defined above, and R3 is a thermally-labile or acid-labile C2-C10 alkyl, C4-C10 alkenyl, or aryl(C1-C10)alkyl group; with a silylating reagent to produce a sulfenate silyl ester of the formula wherein: R1 and R2 are as defined above; R7 is OSi(R)3; and each R is independently C1-C6 alkyl, aryl or arylalkyl; and (2) reacting said sulfenace silyl ester with a mercaptan of the formula HSR8, where R8 is as defined above, in the presence of an amine base. 34. The process of Claim 33 wherein: R1 is hydrogen, C1-C4 alkoxy, or arylalkoxy; and R2 is hydrogen, C1-C4 alkoxy, or arylalkoxy. 35. The process of Claim 34 wherein the amine base is triethylamine, diisopropylethylamine or pyridine. 36. The process of Claim 35 wherein the silylating reagent is bis(trimethylsilyl)urea and R is methyl. 37. The process of Claim 36 wherein R3 is a thermally-labile or acid-labile C2-C10 alkyl group. 38. The process of Claim 37 wherein the amine base is triethylamine. 39 The process of Claim 38 wherein R1 and R2 are methoxy and R3 is t-butyl. 40. The process of Claim 39 wherein R8 is C1-C6 alkyl. 41. The process of Claim 40 wherein R8 is ethyl. 42. The process for the synthesis of a compound of the formula XIII wherein: R9 is hydrogen, halo, amino or hydroxyl; R10 is hydrogen, halo, amino or hydroxyl; R11 and R12 are independently C1-C4 alkyl, or R11 and R12 together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, and morpholino; and HX is HCl or HBr; comprising the steps of: (a) cyclizing in the presence of an acid catalyst a compound of the formula wherein: R1 is hydrogen, C1-C4 alkoxy, arylalkoxy, halo or amino; R2 is hydrogen. C1-C4 alkoxy, arylalkoxy, halo or amino; and R4 is Osi(R)3, NR5R6, or SR8; each R is independently C1-C6 alkyl, aryl or arylalkyl; R5 and R6 are independently hydrogen, C1-C6 alkyl or aryl, or R5 and R6 together with the nitrogen atom lform a ring selected from piperidine, pyrrolidine, morpholine, and hexaniethylimine; and R8 is C1-C6 alkyl, aryl, or arylalkyl; to prepare a benzothiophene compound of the formula I wherein R1 and R2 as defined above; (b) acylating said benzothiophene compound with an acylating agent of the formula XII wherein: R11, R12' and HX are as defined above; and R13 is chloro, bromo, or hydroxyl; in the presence of BX'3, wherein X' is chloro or bromo; (c) when R1 and/or R2 is C1-C4 alkoxy or arylalkoxy, dealkylating one or more phenolic groups of the acylation product of step (b) by reacting with additional BX'3, wherein X' is as defined above; and, optionally, (d) isolating the formula XIII compound.

Description

The invention relates to new vinyl sulfenic acid derivatives and a new method for their preparation. These compounds are used to synthesize benzo [b] thiophenes, especially 2arylbenzo [b] thiophenes.

Benzo [b] thiophenes are prepared in many different synthetic ways. One of the most widely used methods is the cyclization of o-mercaptocinnamic acids. This method is limited to the production of benzo [b] thiophene-2-carboxylates. 2-Phenylbenzo [b] thiophenes are obtained by cyclization of 2phenylthio acetaldehyde 2 acid-catalyzed dialkyl acetals. Unsubstituted benzo [b] thiophenes are obtained by the catalytic condensation of styrene and sulfur.

3- Substituted benzo [b] thiophenes are obtained by cyclization of acid catalyzed ariptiomethylketones; however, this method is limited to the production of 3-alkylbenzo [b] thiophenes. See Campaigne, Thiophenes and their Benzo Derivatives: (iii) Synthesis and Applications, in Comprehensive Hetercyclic Chemistry (Katritzky and Rees, eds.), Volume IV, Part III, 863-934 (1984). 3Chlor-2-phenylbenzo [b] thiophene is obtained by the reaction of diphenylacetylene with sulfur dichloride. Barton and Zika, J. Org. Chem., 35, 1729-1733 (1970). Benzo [b] thiophenes are also obtained by the pyrolysis of styryl sulfoxides. However, low yields and extremely high temperatures make this method unacceptable for synthesis on an industrial scale. See Ando, J. Chem. Soc., Chem. Comm., 704-705 (1975).

Sulfenic acids are believed to be key intermediates of many chemical reactions; however, there are very few examples of the isolation of these compounds. See Shelton and Davis, J. Am. Chem. Soc., 89 (3), 718719 (1968) and Davis et al., J. Am. Chem. Soc., 100, 2844 (1 978). Sulfenic acids are prepared in situ and cyclized intramolecularly or intermolecularly with olefins and acetylenes. See, Maz-zanti et al., J. Chem. Soc., Perkin Trans. 1, 3299-3004 (1944) and Davis et al., J. Org. Chem., 45, 1650-1653 (1980). A number of trimethylsilyl arenosulfenates are prepared from the corresponding N-benzylidene arenesulfinamides; however, the yields of trimethylsilyl ethers are usually very low. Davis et al., J. Org. Chem., 45, 1650-1653 (1980).

The preparation of 6-hydroxy-2- (4-hydroxyphenyl) benzo [b] thiophenes is described in US Pat. No. 4,133,814 and 4,380,635. One of the methods described in these patents is acid-catalyzed intramolecular cyclization / rearrangement (3-methoxyphenylthio -4 methoxyacetophenone. The reaction of this starting compound in neat polyphosphoric acid at from about 85 ° C to about 90 ° C gives approximately 3: 1 mixture of regioisomerase products: 6-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene and 4-methoxy-2 - (4methoxyphenyl) benzo [b] thiophene. These isomeric benzo [b] thiophenes co-precipitate from the reaction mixture, yielding a mixture containing both compounds. To obtain an individual isomer, regioisomers must be separated by methods such as chromatography or fractional crystallization. Therefore, at present there is a need for an effective and regioselective synthesis of 2 arylbenzo [b] thiophenes from readily available starting materials.

The present invention relates to new derivatives of vinyl sulfenic acids: the new silyl esters of sulfenic acids, sulfenamides and disulfides, and to a method for the preparation of derivatives of vinyl sulfones acids. In particular, the present invention relates to compounds of formula III

wherein

R _one represents hydrogen, C _one -WITH _four alkoxy, arylalkoxy, halogen or amino group;

R ₂ represents hydrogen, C _one -WITH _four alkoxy, arylalkoxy, halogen or amino group;

R _four - OSi (R) ₃ , NR _five R ₆ or SR _eight ;

each R, independently, is C _one C6-alkyl, aryl or arylalkyl;

R _five and R ₆ independently represent hydrogen, C _one -WITH ₆ -alkyl, arylalkyl or aryl, or R _five and R6 together with the nitrogen atom form a ring selected from piperidine, pyrrolidine, morpholine or hexamethylamine; and

R _eight represents C _one -WITH _four -alkyl, aryl or arylalkyl.

Therefore, the present invention includes the individual isomers E and Z, or mixtures thereof of formula III. These E and Z regioisomers are represented by the following structures:

Another object of the present invention is a method for producing silylsulfenates, sulfenamides and disulfides. The present invention relates to a method for producing a compound of formula III

III in which

Ri represents hydrogen, C (-C _g alkoxy, arylalkoxy, halogen or amino group;

R ₂ represents hydrogen, C _one -WITH _four alkoxy, arylalkoxy, halogen or amino group;

R4 represents OSi (R) ₃ , NR _five R ₆ or SR _eight ; each R, independently, is C _one -WITH _four alkyl, aryl or arylalkyl;

R _five and R ₆ independently represents hydrogen, C _one -WITH ₆ -alkyl, arylalkyl or aryl, or R _five and R ₆ together with the nitrogen atom form a ring selected from piperidine, pyrrolidine, morpholine or hexamethylamine; and

R _eight represents C _one -WITH ₆ -alkyl, aryl or arylalkyl;

which includes:

(1) the reaction of compounds of formula II

in which r _one and R ₂ defined above and

R3 is thermally or acid unstable. ₂ -WITH _ten -alkyl, C _four -WITH _ten -alkenyl or aryl (C _one -WITH _ten a) alkyl; with silylating reagent to obtain silylsulfenate formula IV

wherein

R1 and R2 are as defined above;

R ₇ represents OSi (R) ₃ ; and each R, independently, represents C1C6-alkyl, aryl or arylalkyl;

(2) optionally reacting the resulting silylsulfenate with an amine of the formula HNR _five R ₆ in which R _five and R ₆ defined above; or (3) optionally reacting silylsulfenate with a mercaptan of formula HSR _eight in which R _eight as defined above, in the presence of an amine base.

One of the objects of the present invention is a method for producing silylsulfenate formula IV. In particular, the present invention relates to a method for producing a compound of formula IV

wherein

R represents hydrogen, C _one -WITH _four alkoxy, arylalkoxy, halogen or amino group;

R ₂ represents hydrogen, C _one -WITH _four alkoxy, arylalkoxy, halogen or amino group;

R7 is OSi (R) 3, each R is independently C1-C6 alkyl, aryl or arylalkyl, which involves the reaction of a compound of formula II

in which R1 and R2 are defined above, and

R3 is thermally or acid-unstable C2-C10-alkyl,

C4-C10 is alkenyl or aryl (C110) alkyl; with silylating reagent.

Another object of the present invention is a method for producing sulfenamide formula V, in particular, the present invention relates to a method for producing a compound of formula V

wherein

R _one represents hydrogen, C _one -WITH _four alkoxy, arylalkoxy, halogen or amino group;

R ₂ represents hydrogen, C _one -WITH _four alkoxy, arylalkoxy, halogen or amino group;

R _five and R ₆ , independently represent hydrogen, C _one -WITH ₆ -alkyl, arylalkyl or aryl, or R _five and R ₆ together with the nitrogen atom form a ring selected from piperidine, pyrrolidine, morpholine or hexamethylamine, which includes:

(1) the reaction of the compounds of formula II:

in which R1 and R2 are defined above, and

R3 is thermally or acid unstable. ₂ -WITH _ten -alkyl, C _four -WITH _ten -alkenyl or aryl (C _one -WITH _ten a) alkyl; with silylating reagent to obtain silylsulfenate formula IV

wherein

R1 and R2 are as defined above;

R7 is OSi (R) 3; and each R, independently, represents C1C6-alkyl, aryl or arylalkyl;

(2) the reaction of the obtained silylsulfenate with an amine of the formula HNR _five R ₆ in which R _five and R ₆ defined above.

Another object of the present invention is a method for producing disulfides of the formula XIV. In particular, the present invention relates to a method for producing a compound of formula XIV

wherein

Ri is hydrogen, C _g WITH _four alkoxy, arylalkoxy, halogen or amino group;

R ₂ represents hydrogen, C _one -WITH _four alkoxy, arylalkoxy, halogen or amino group;

R _eight represents C _one -WITH ₆ -alkyl, aryl or arylalkyl, which includes (1) the reaction of compounds of formula II:

in which r _one and R ₂ defined above and

R ₃ is thermally or acid unstable C ₂ -WITH _ten -alkyl, C _four -WITH _ten -alkenyl or aryl (C _one -WITH _ten a) alkyl;

with silylating reagent to obtain silylsulfenate formula IV

wherein

R1 and R2 are as defined above;

R ₇ represent OSi (R) ₃ ; and each R is independently C _one -WITH ₆ alkyl, aryl or arylalkyl; and (2) the reaction of the obtained silylsulfenate with a mercaptan of the formula HSR _eight in which R _eight as defined above, in the presence of an amine base.

Another object of the invention is a method for the synthesis of compounds of formula XIII

in which r ₉ represents hydrogen, halogen, amino group or hydroxy group;

R1 0 represents hydrogen, halogen, amino group or hydroxy group;

R _eleven and R ₁₂ independently represent C _one -WITH _four -alkyl, or R _eleven and R ₁₂ together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethylenimino and morpholino; and

HX is NSH or HBg, which includes:

(a) cyclization in the presence of an acid catalyst of a compound of formula III

wherein

R _one represents hydrogen, C _one -WITH _four alkoxy, arylalkoxy, halogen or amino group;

R ₂ represents hydrogen, C _one -WITH _four alkoxy, arylalkoxy, halogen or amino group;

R _four represents OSi (R) ₃ , NR _five R ₆ or SR _eight ; each R is independently C1-C4 alkyl, aryl or arylalkyl;

R5 and R6 independently represent hydrogen,

WITH _one -WITH ₆ -alkyl or aryl, or R _five and R ₆ together with the nitrogen atom form a ring selected from piperidine, pyrrolidine, morpholine or hexamethylamine; and

R _eight represents C _one -WITH ₆ -alkyl, aryl or arylalkyl;

to form a benzothiophene compound of formula I

in which R1 and R2 are defined above;

(b) acylation of the indicated benzothiophene compound by an acylating reagent of formula XII

XII in which

R _eleven and R ₁₂ and HX are defined above; and

R ₁₃ is chlorine, bromine or hydroxy, in the presence of BX ' ₃ in which X 'represents chlorine or bromine;

(c) if R _one and / or R ₂ represents C _one -WITH _four alkoxy group or aryloxy group, dealkylation of one or more phenolic groups of the acylation product from step (b) by reaction with an additional amount of BX ' ₃ in which X 'is defined above; and (g) isolating a compound of formula XIII.

The term acid catalyst refers to a Lewis acid or a Bronsted acid. Typical Lewis acids are zinc chloride, zinc iodide, aluminum chloride and aluminum bromide. Typical Brønsted acids include inorganic acids such as sulfuric and phosphoric acid; carboxylic acids such as acetic and trifluoroacetic acids; sulfonic acids, such as methanesulfonic, benzenesulfonic, 1-naphthalenesulfonic, 1-butane sulfonic, ethanesulfonic,

4-ethylbenzene sulfonic, 1-hexane sulfonic, 1,5-naphthalene disulfonic, 1-octane sulfonic, 7 new, camphorsulfonic, trifluoromethanesulfonic and p-toluenesulfonic acid;

and polymeric arylsulphonic acids, such as Nafion ^one ''. Amberlist ^to or Amberlite ^to . Preferred acids for use in catalyzing the processes of the present invention are sulfonic 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.

The term (D-Cd-alkoxy group means a group such as a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a n-butoxy group, a tert-butoxy group, and the like. The term halogen refers to fluorine, chlorine, bromine or iodine.

The term C1-C ₆ -alkyl means a straight or branched alkyl chain having from one to six carbon atoms. Typical C _one -WITH ₆ -alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, 2-methylpentyl, and similar groups. Term C _one -WITH _four -alkyl means a straight or branched alkyl chain having from one to four carbon atoms and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

The term aryl refers to groups such as phenyl and substituted phenyl. The term substituted phenyl means phenyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy group, nitro group. WITH _one -WITH _four -alkyl, C _one -WITH _four -alkoxy, trichloromethyl and trifluoromethyl. Examples of the substituted phenyl group include 4-chlorophenyl, 2,6 dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4bromophenyl, 3,4-dibromophenyl, 3-chloro-4fluorophenyl, 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-tert-butylphenyl , 3-fluoro-2-methylphenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 2,6-dimethylphenyl, 2-fluoro-5methylphenyl, 2,4,6-trifluorophenyl, 2-trifluoromethylphenyl, 2-chloro-5 trifluoromethylphenyl, 3,5bis (trifluoromethyl) phenyl, 2-metho xyphenyl, 3methoxyphenyl, 3,5-dimethoxyphenyl, 4-hydroxy-3-methylphenyl, 3,5-dimethyl-4-hydroxyphenyl, 2-methyl-4-nitrophenyl, 4-methoxy-2 nitrophenyl, and others.

The term arylalkyl means C _one -WITH _four an alkyl group substituted by one or more aryl groups. Representatives of this group include benzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl (such as chlorobenzyl, p-bromo-benzyl, 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 others.

The term arylalkoxy refers to _one -WITH _four alkoxy group substituted by one or more aryl groups. Representatives of this group include benzyloxy, onitrobenziloksi, p-nitrobenzyloxy, p-galogenbenziloksi (such as p-chlorobenzyloxy, pbrombenziloksi, p-iodbenziloksi) -feniletoksi 1, 2-phenylethoxy, 3-phenylpropoxy, 4fenilbutoksi, 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) methyl , bis (2-nitrophenyl) methoxy and others.

Term thermally or acid unstable ₂ -WITH _one o-alkyl, C _four -WITH _one o-alkenyl or aryl (C _one -WITH _ten ) alkyl means a group that is easily cleaved from the sulfoxide (SO) group when heated or treated with an acid catalyst.

Thermally or acid unstable C ₂ WITH _1o -alkyl groups have a normal or branched alkyl chain having from two to ten carbon atoms and having at least one hydrogen atom in the beta position. Typical thermally or acid-unstable C 2 -C 1 o-alkyls include ethyl, npropyl, isopropyl, 1,1-dimethylpropyl, nbutyl, sec-butyl, tert-butyl, 1,1-dimethylbutyl, 2-methylbutyl, 3-methylbutyl, 1methylbutyl, 1,2 -dimethylbutyl, 1,3-dimethylbutyl, 2,4-dimethylbutyl, 3,3-dimethylbutyl, npentyl, 1-methyl-pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-hexyl and others.

Thermally or acid unstable C _four C 1 alkenyl groups have straight or branched alkenyl chains having from four to ten carbon atoms, at least one unsaturation site and either beta hydrogen or delta hydrogen. Typical thermally or acid-unstable C _four -WITH _1o -alkenyl groups 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, 3methyl-2-pentenyl, 4-methyl-2-pentenyl, 2-methyl3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3pentenyl, 2-methyl-4-pentenyl, 3-methyl-49 pentenyl , 4-methyl-4-pentenyl, 2-hexenyl, 3hexenyl, 4-hexenyl, 5-hexenyl, and others.

The term thermally or acid unstable aryl (C _g WITH _ten a) alkyl is thermally or acid unstable. ₂ -WITH _ten -alkyl groups, additionally containing one or more aryl groups and aryl-substituted methyl groups. Typical aryl (C1C _ten a) alkyl groups include benzyl, diphenylmethyl, triphenylmethyl, p-methoxybenzip, 2-phenylethyl, 2-phenylpropyl, 3-phenylpropyl, and others.

One group of compounds of the present invention is silylsulfenate. In particular, the compounds of formula III, where R _four represents OSi (R) ₃ and each R, independently of one another, is C _one -WITH ₆ -alkyl, aryl, ipyl, arylalkyl, and the compounds of formula IV are silylsulfenate. Preferred silylsulfenate named by abbreviations of the nomenclature known in chemistry, as shown in the following table.

Table 1

Abbreviation Silyl group Tms Trimethylsilyl TPP Triethylsilyl TIPS Triisopropylsilyl DMIPS Dimethylisopropylsilyl DEIPS Diethylisopropylsilyl DMGS Dimethylhexylsilyl TBDMS Tert-butyldimethylsilyl TBDFS Tert-butyldiphenylsilyl TBS Tribenzylsilyl TFS Triphenylsilyl DFMS Diphenylmethylsilyl TBMFS Tert-butyldi (methoxyphenyl) silyl

The term silylating reagent refers to a compound or combination of compounds used to convert an intermediate sulfenic acid to silyl sulfenates.

Typical silylating agents include bis (trialkylsilyl) urea, such as 1, 3-bis (trimethylsilyl) urea,, 3-bis (triethylsilyl) urea, 1, 3-bis (dimethylisopropylsilyl) urea, 3-bis (triisopropylsilyl) urea, 1, 3bis (diethylisopropylsilyl) urea, 1, 3-bis (dimethylhexylsilyl) urea and

1.3-bis (tert-butyldimethylsilyl) urea; bis (triarylsilyl) urea, such as 1,3bis (triphenylsilyl) urea;

bis (diarylalkylsilyl) urea, such as 1,3-bis (diphenylmethylsilyl) urea and

1.3-bis (tert-butyldiphenylsilyl) urea; and hexaalkyldisilazanes such as hexamethyldisilazane; or a combination of hexaalkyldisilylazan and a catalytic amount of a trialkylsilyl chloride, such as chlorotrimethylsilane.

The compounds of formula III exist in two regioisomeric forms, E and Z. These E and Z regioisomers are represented by the following

The starting compounds for the processes of the present invention can be obtained in various ways. One method for preparing compounds of formula II is shown in Scheme 1.

Typically, a compound of formula VII is converted to styryl sulfide by reaction with a mercaptan of formula HSR ₃ in the presence of Lewis acid. The compound of formula VIII is then oxidized to styryl sulfoxide of formula II.

In more detail, the compound of formula VII, in which R _one and R ₂ as defined above, is treated with a Lewis acid, such as titanium (IV) chloride. This reaction is carried out in an anhydrous organic solvent, such as tetrahydrofuran, at a temperature of from 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 HSR ₃ where R ₃ represents a thermally or acid-unstable group C ₂ -WITH _ten -alkyl, C _four WITH _ten -alkenyl or aryl (C _one -WITH _ten ) alkyl. Preferably, the mercaptan and amine base are added as a solution in the reaction solvent. The amine base is triethylamine. After adding the mercaptan and amine base, the reaction mixture is heated to a temperature of from 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 chemistry, such as crystallization or chromatography.

The compound of formula VIII, where R _one R ₂ and R ₃ defined above, then oxidized to obtain compounds of formula II. Suitable oxidizing agents for this reaction are peracids, such as peracetic acid and m-chloroperoxybenzoic acid and hydrogen peroxide. This oxidation reaction is usually carried out in an organic solvent, such as toluene, methylene chloride, chloroform or carbon tetrachloride. If peracid is used as the oxidizing agent, the reaction is usually carried out at a temperature of from about -30 ° C to about 15 ° C, preferably at about -20 ° C. The reaction products are easily purified by recrystallization. If r ₃ is tert-butyl, the crystalline product of this reaction sequence is the regioisomer E of formula II.

If r ₃ has tertiary carbon combined with a sulfur atom, then the regioisomer Z of compounds of formula II can be obtained selectively along the second path, as shown in Scheme 2.

Typically, a benzyl alcohol of formula IX is reacted with a mercaptan of formula R ₃ SH to form a benzyl sulfide of formula X. Benzyl sulfide is reacted with a strong base to form a benzyl anion, which is condensed with benzaldehyde. The condensation product is reacted with acyl chloride and the resulting intermediate product is treated with a second strong base to obtain the styryl sulfide of formula VIIIZ. This styryl sulfide is then oxidized with an oxidizing agent to give compound IIZ.

The first step in the synthesis of Z-styryl sulfoxide compounds is the conversion of benzyl alcohol to benzyl sulfide of formula X. The reaction of a compound of formula IX, where R2 is defined above, with a mercaptan of formula R ₃ SH in which R ₃ is thermally or acid unstable C ₂ -WITH _ten -alkyl, C _four -WITH _ten alkenyl or aryl (C _one -WITH _ten ) alkyl having a tertiary carbon atom adjacent to a sulfur atom, in the presence of a Lewis acid, gives a benzyl sulfide of formula X. Suitable Lewis acids for this transformation are zinc bromide, zinc chloride, zinc iodide, ferric chloride, titanium chloride (IV), aluminum trichloride and tribromide aluminum, preferably zinc iodide. The reaction is usually carried out in an organic solvent, such as 1, 2 dichloroethane or methylene chloride. If the reaction is carried out at room temperature, then the reaction is completed after 18 h.

Benzyl sulfide is reacted with a strong base to form a benzyl 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 lithium alkyls such as n-butyl lithium, tert-butyl lithium, sec-butyl lithium, and methyl lithium. The preferred strong base for this reaction is n-butyl lithium. The preferred solvent for this reaction is tetrahydrofuran. If n-butyl lithium is used as a strong base, the reaction is carried out at a temperature of from about -35 ° C to about -15 ° C.

The benzyl anion is condensed with benzaldehyde to form an intermediate condensation product. Benzaldehyde has the general formula p ^ (C ₆ H _four ) CHO, in which R _one represents hydrogen, C _one -WITH _four -alkoxy, arylalkoxy, halogen or amino. Preferably, a benzyl anion is obtained and the condensation product is formed in situ by adding benzaldehyde to a cold solution of the benzyl anion.

The condensation product is treated with an acid chloride to form an intermediate. Representative acid chlorides include acyl chlorides such as acetyl chloride and benzoyl chloride; sulphonyl chlorides such as methanesulphonyl chloride, benzenesulphonyl chloride, 1 -butanesulphonyl chloride, ethanesulphonyl chloride, isopropylsulphonyl chloride and p-toluenesulphonyl chloride; alkoxycarbonyl chlorides such as methoxycarbonyl chloride and benzyloxycarbonyl chloride; and dialkylaminocarbonyl chlorides, such as ^ dimethylaminocarbonyl chloride; preferably sulfonyl chloride. Preferably, methanesulfonyl chloride is added to the reaction mixture soon after the formation of the condensation product.

The intermediate is reacted with a second strong base to produce a styryl sulfide of formula VIIIZ, where R _one R ₂ and R3 are 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; and lithium alkyls 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. Usually, this reaction is carried out at a temperature of from about 1.5 ° C to about room temperature, preferably at room temperature.

Steryl sulfide is oxidized to give 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. The preferred oxidizing agent is peracetic acid. The oxidation is usually 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 of from about -40 ° C to about 0 ° C.

Alternatively, if R ₃ has a tertiary carbon atom adjacent to the sulfur atom, the benzyl sulfide intermediate (compound of formula X) can be used to obtain a mixture of E and Z isomers of styryl sulfoxides of formula II. This synthesis is depicted in scheme 3:

above, is oxidized to give the corresponding benzyl sulfoxide. This benzyl sulfoxide is reacted with a strong base and the resulting anion is condensed with benzaldehyde. The condensation product is reacted with an acid chloride and the resulting intermediate is reacted with a second strong base to produce styryl sulfoxide.

Benzyl sulfide of the formula X, in which R ₂ defined above and R ₃ is thermally or acid-resistant C ₂ -WITH _ten -alkyl, C _four WITH _ten -alkenyl or aryl (C _one -WITH _ten ) alkyl having a tertiary carbon atom adjacent to a sulfur atom is oxidized to give the corresponding benzyl sulfoxide of formula XI.

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. The oxidation is usually 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 from about -35 ° C to about 5 ° C.

Benzyl sulfoxide, a compound of formula XI, in which R2 and R3 are defined above, is reacted with a strong base to form a benzyl 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, tert-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 transformation is n-butyl lithium. The 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 benzyl anion is condensed, without isolation, with a benzaldehyde compound of the formula n ^^ CbNDSNO, in which R _one defined above. Preferably, about one equivalent of benzaldehyde is added to the cold solution prepared as described in the previous paragraph. The resulting diastereomeric mixture of condensation products can be isolated or, preferably, used in the next stage without isolation.

The condensation product reacts with an acid chloride to produce an intermediate. The condensation product is optionally treated with a base, such as n-butyl lithium, and reacted with an acid chloride. Representatives of acid chlorides include acyl chlorides, such as acetyl chloride and benzoyl chloride; sulphonyl chlorides such as methanesulphonyl chloride, benzenesulphonyl chloride, 1 -butanesulphonyl chloride, ethanesulphonyl chloride, isopropylsulphonyl chloride and p-toluenesulphonyl chloride; alkoxycarbonyl chlorides such as methoxycarbonyl chloride and benzyloxycarbonyl chloride; and dialkylaminocarbonyl chlorides, such as N, Ndimethylaminocarbonyl chloride; preferably sulfonyl chloride. The acid chloride is added to the cold reaction mixture and the resulting mixture is allowed to warm to room temperature. Preferably, methanesulfonyl chloride is added to the reaction mixture soon after the formation of the condensation product, which eliminates the need to add additional base.

The resulting intermediate is reacted with a second strong base to produce E- and Z-styryl sulfoxide of formula II, where R _one R ₂ and R ₃ defined above. Suitable 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; and alkyl lithiums such as n-butyl lithium, tert-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. Preferably a 20% excess is added, such as 1.2 equivalents of a second base. Usually, the reaction is carried out at a temperature of from about 15 ° C to about room temperature, preferably at room temperature.

The compounds of the present invention can be prepared from compounds of the formula II. New silylsulfenates are obtained from styryl sulphoxides as shown in Scheme 4.

Usually, silylsulfenate, where R _one R ₂ and R ₇ defined above and R ₃ - thermally or acid unstable C ₂ -WITH _one o-alkyl, C _four -WITH _ten -alkeny l or aryl (C _one -WITH _ten ) alkyl, is obtained by reacting a compound of formula II with a silylating reagent. Suitable solvents for this reaction include benzene, toluene, xylene, and high-boiling halogenated hydrocarbon solvents having a boiling point greater than or equal to 80 ° C, such as 1,1,2 trihloroethane. Suitable silylating agents include bis (trialkylsilyl) urea, 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, and 1,3-bis (t-butyldimethylsilyl) urea; bis (triarylsilyl) ureas, such as 1,3-bis (triphenylsilyl) urea; bis (dialkylarylsilyl) urea, such as 1, 3bis (diphenylmethylsilyl) urea and 1, 3bis (tert-butyldiphenylsilyl) urea; and hexaalkyldisilazanes such as hexamethyldisilazane;

or a combination of hexaalkyldisilylazan and a catalytic amount of a trialkylsilide chloride, such as trimethylsilyl chloride.

For best results, after the addition is completed, the final concentration of the compound of formula II is from about 0.001 M to about 0.5 M. Preferably a slight excess, such as 10.0 percent, of the silylating agent is used. This reaction can be carried out at from about 80 ° C to about 1 40 ° C for from about ten minutes to about two hours. Since the Z isomer reacts significantly faster than the corresponding E-isomer, using only the Z-isomer as the starting compound requires less time for complete conversion.

New sulfenamides are obtained from silylsulfenate as shown in Scheme 5.

Usually, silylsulfenate, where R _one R ₂ and R ₇ as defined above, prepared from styryl sulfoxide and, preferably without isolation or purification, is reacted with an amine of the formula HNR _five R ₆ where R _five and R ₆ defined above. Usually, silylsulfenate is obtained, the reaction mixture is cooled to from about 0 ° C to about 50 ° C and treated with an amine. Preferably, one to two equivalents of amine are used. The conversion from silyl ether to sulfenamide usually completes in about two to eight hours. The resulting sulfenamides can be purified by standard organic chemistry methods such as silica gel chromatography.

New disulfides are obtained from silylsulfenate as shown in scheme 6.

Usually, silylsulfenate, where R _one R ₂ and R ₇ as defined above, is prepared from styryl sulfoxide and, preferably without isolation and purification, is reacted with a mercaptan of the formula HSR _eight where R _eight as defined above, in the presence of an amine base. Preferably, silylsulfenate is obtained, the reaction solution is allowed to cool to room temperature, and the reaction mixture is treated with a solution containing mercaptan and amine base. The solvent for obtaining the mercaptan / amine solution is the same as the solvent for the silyl sulfenate-containing mixture. Typical amine bases of triethylamine, diisopropylethylamine, pyridine, morpholine, Nmethylmorpholine and collidine. The conversion of silylsulfenate usually completes in about one to eight hours. The resulting disulfides can be purified by standard organic chemistry methods such as silica gel chromatography.

Intermediate silylsulfenates, sulfenamides and disulfides are useful for the synthesis of 2 arylbenzo [^ thiophenes as shown in Scheme 7.

Typically, silylsulfenates, sulfenamides or disulfides are treated with acidic catalysts to give compounds of Formula I. Suitable acidic catalysts for this reaction include Lewis acids or Bronsted acids.

Typical Lewis acids are zinc chloride, zinc iodide, aluminum chloride and aluminum bromide. Typical Brønsted acids include inorganic acids such as sulfuric acid and phosphoric acid, carboxylic acids such as acetic acid and trifluoroacetic acid; sulfonic acids, such as methanesulfonic, benzenesulfonic, 1-naphthalenesulfonic, 1-butanesulfonic, ethanesulfonic, 4-ethylbenzenesulfonic, 1 -hexanesulfonic, 1,5-naphthalene disulfonic, 1-octane sulfonic, camphorsulfonic, trifluoromethane-sulfentane-sulfantenthenesulfonic sulfonate-sulfonate-sulfonic sulfonate-sulfonic sulfonic sulfonate sulfonate sulfonate sulfonate sulfonic acid sulfonate sulfonate sulfonate sulfonic sulfonate sulfonic sulfonate sulfonate sulfonic sulfonate sulfonate sulfonate sulfonic sulfonate sulfonate sulfonate sulfonate and polymeric arylsulphonic acids, such as Nafion ^to Amberlist ^to or Amberlite ^to . More 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 an 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 from about 80 ° C to about 140 ° C and treated with a solution of silyl sulphenate, sulfenamide or disulfide in the same solvent. An excess amount of acid catalyst is used, preferably three equivalents of acid. For best results, the final concentration of the starting compound is from about 0.01 M to about 0.2 M, preferably 0.05 M. In addition, the best yields are obtained if silylsulfenate is slowly added to the heated acid solution for from about 1 to 5 minutes up to about three hours. For best results, residual water is removed from the reaction solution using a Dean-Stark trap and Soxhlet extractor. Steryl sulfoxides are also used to prepare benzothiophenyl styrylsulfide as shown in Scheme 8.

Benzothiophenyl styryl sulfides, where Ri and R2 are defined above, are obtained from styryl sulphoxides. Usually, a solution of styryl sulfoxide, where R _one and R ₂ defined above and R ₃ is thermally or acid unstable C ₂ -WITH _ten alkyl, C _four -WITH _ten -alkenyl or aryl (C _one -WITH _ten ) alkyl, is added to the acidic catalyst solution at a temperature of from about 100 ° C to about 140 ° C, with the acid catalyst 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. If styryl sulfoxide is present at a final concentration of about 0.2 M and is added within six hours, then the acid concentration is about 0.002 M. After about one to two hours, significant amounts of compounds of Formula VI are present in the reaction. A long reaction time results in compounds of formula I.

These compounds of formula VI can then be converted into compounds of formula I by treating with an additional amount of acid, such as from about 0.5 to about three equivalents, and heating to about 1 00 ° C 1 40 ° C. The concentration of the compound of formula VI is in the range of from about 0.01 M to about 0.5 M. Suitable solvents for both forming compounds of formula VI and converting them to compounds of formula 1 include toluene, xylene and 1,2-dichloroethane.

The compounds of formula I are useful as intermediates in the synthesis of a number of 3aroyl-2-arylbenzo [b] thiophenes. U.S. Patents 4,133,814 and 4,418,068, which are incorporated herein by reference, describe these 3aroyl-2-arylbenzo [b] thiophenes and methods for their preparation from compounds of formula I. Improved synthesis of such 3-aroyl-2arylbenzo [b] thiophenes from compounds of formula 1, in which R _one and R ₂ represents hydrogen, C _one C4-alkoxy or arylalkoxy is shown in Scheme 9.

The compound of formula I, in which R _one and R ₂ represent hydrogen; C1-C4-alkoxy or arylalkoxy group, acylated with a compound of formula XII, in which R ₁₃ is chlorine or hydroxy, in the presence of boron trichloride or boron tribromide; boron trichloride is preferred. The reaction can be carried out in many organic solvents, such as chloroform, methylene chloride, 1,2-dichloroethane, 1,2,3trichloropropane, 1,1,2,2-tetrachloroethane, 1,2dichlorobenzene, chlorobenzene and fluorobenzene. The preferred solvent for this synthesis is 1,2-dichloroethane. The reaction is carried out at a temperature of from about -10 ° C to about 25 ° C, preferably at 0 ° C.

The reaction proceeds best at a concentration of benzothiophene of formula I from about 0.2 M to about 1.0 M. The acylation reaction usually ends in about 2-8 hours.

If Rj and / or R ₂ represents C _one -WITH _four alkoxy - or arylalkoxygroup, acylated benzothiophene is preferably converted into a compound of formula XIII, in which R _five and / or R represents a hydroxy group, without isolating the product from the acylation reaction. This conversion is carried out by adding an additional amount of boron trichloride or boron tribromide and heating the reaction mixture. Preferably, two to five molar equivalents of boron trichloride are added to the reaction mixture, most preferably three molar equivalents. The reaction is carried out at a temperature of from about 25 ° C to about 40 ° C, preferably at 35 ° C. The reaction usually ends in about 4-48 hours.

The acylation reaction or the acylation / dealkylation reaction is stopped with an alcohol or 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 ethanol (ethanol 3A) and methanol 95: 5. Ethanol FOR can be at room temperature or heated to boiling point. When the reaction is stopped in this manner, the compound of formula XIII usually crystallizes from the resulting alcohol mixture. Usually use 1.25-3.75 ml of alcohol per millimole of benzothiophene starting material.

The following examples illustrate the present invention. The examples do not limit the scope of the present invention and should not be so construed. All experiments were carried out with a positive pressure of dry nitrogen. All solvents and reagents were used as obtained. The percentage composition is usually calculated on a weight (w / w) basis; with the exception of high performance liquid chromatography (HPLC) solvents, which are calculated on a volume basis. Proton nuclear magnetic resonance spectra ( ^one H NMR) and spectra ¹³ With nuclear magnetic resonance ( ¹³ With NMR) is obtained on a Bruker AC-300 FINMR spectrometer at 300, 135 MHz or at 75.469 MHz for proton and carbon, respectively, or on a spectrometer

GE QE-300 at 300.15 MHz. Silica gel flash chromatography was performed as described by Still et ak using Silica Gel 60 (230400 mesh, E. Merk). Still et al., J. Org. Chem., 43, 2923 (1978). Elemental analyzes for carbon, hydrogen, and nitrogen were performed on a 440 element equipment analyzer from Control Equipment Corporation. Elemental analyzes for sulfur were performed on a Brinkman colorimetric elemental analyzer. Melting points were determined in open glass capillaries on a Mel-Temp 11 melting point device or on a Mettler FP62 automatic device and taken without correction. Field desorption mass spectra (MRTDs) were obtained using Varian Instruments VG 70-SE or VG ZAB-3F mass spectrometers. High-resolution free-atom bombardment mass spectra (FMSA) were obtained on a Varian Instruments VG ZAB-2SE mass spectrometer.

The in situ yields of 6-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene were determined by high performance liquid chromatography (HPLC) compared with an authentic sample of this compound obtained by known methods. See US Pat. No. 4,133,814. Typically, samples of the reaction mixture were diluted with acetonitrile and the diluted samples were analyzed by HPLC using a Zorbax column. ^R RX-C8 (4.6 mm x 25 cm) and UV detection (280 nm). For these analyzes, the following linear gradient solvent system was used.

Solvent gradient system

Time (min) BUT (%) AT (%) 0 50 50 2 50 50 20 20 80 35 20 80 37 50 50 45 50 50

A: 0.01 M aqueous solution of sodium phosphate (pH 2.0);

B: acetonitrile.

The amount (percentage) of 6-hydroxy-2- (4-hydroxyphenyl) -3 [4- (2-piperidinoethoxy) benzoyl] benzo [b] thiophene hydrochloride in the crystalline material (content) was determined by the following method. A sample of a crystalline solid (5 mg) was weighed into a 1,00 ml volumetric flask and dissolved in a mixture of 75 mM potassium phosphate buffer (pH 2.0) and 70/30 acetonitrile (v / v). An aliquot of solution (10 ml) was analyzed by HPLC using a Zorbax column. ^R RX-C8 (25 cm x 4.6 mm (internal diameter), particle 5 m) and UV detection (280 nm). The following gradient solvent system was used:

Gradient solvent system (content)

Time (min) BUT (%) AT (%) 0 70 thirty 12 70 thirty 14 25 75 sixteen 70 thirty 25 70 thirty

A: 75 mM KN buffer ₂ Ro _four (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 peak area, slope (m) and cut-off section (b) of the calibration curve by the following equation:

peak area - b sample volume (ml)% content = ------------------------ x ------------- -------------- 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 a 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 on a gas chromatograph using a DB Wax column (30 mm x 0.53 mm (internal diameter), (particle 1 m), flow rates through the column were 10 ml / min., And flame ionization detection. The column was heated from 35 to 230 ° C for 12 minutes, the amount of solvent was determined by comparison with the internal standard (2butanol).

Example 1. E-tert-Butyl (4,4'-dimethoxystilbenyl) sulfoxide.

A. Preparation of E-tert-butyl (4,4'-dimethoxystilbenyl) sulphide.

A solution of deoxyanisoin (12.82 g) in tetrahydrofuran (100 ml) was treated with chloride, titanium (IV) (10.43 g). During the addition of titanium (IV) chloride dropwise, the reaction mixture was cooled to maintain the temperature below 35 ° C. After the addition was complete, the mixture was stirred at 30 ° C. After 30 minutes, the 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 50 ° C. After two hours, the mixture was added to a 10% sodium carbonate solution (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 crystallizes after cooling to room temperature. The crystalline product was recrystallized from hot ethanol to obtain 12.3 g of the title compound. Melting point 71-73 ° C.

Calculated for С ^ ЩЮ ^; C 73.13; H 7.36; S 9.76.

Found: C, 73.37; H 7.51; S 9.87.

B. Preparation of E-tert-butyl (4,4'-dimetho-stilbenyl) sulfoxide.

The crystalline compound obtained in Example 1A 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 wt.% In dilute acetic acid, 1.24 g) for 10 minutes. The resulting mixture was extracted with a saturated solution of sodium sulfite and a saturated solution of sodium chloride. The organic phase was concentrated in vacuo. The residue was recrystallized from ethyl acetate / heptane to obtain 14.11 g of the target compound. Melting point 104 ° C (decomp.).

Calculated for C20H24O3S: C 69.74; H 7.02; S 9.31.

Found: C 69.47; H 7.04; S 9,54.

Example 2. Z-tert-Butyl (4,4'-dimethoxystilbenyl) sulfoxide.

A. Preparation of tert-butyl (4-methoxybenzyl) sulfide.

A mixture of 4-methoxybenzyl alcohol (10.13 g) and zinc iodide (11.7 g) in 1,2-dichloromethane (1 20 ml) was treated with 2-methyl-2-propanethiol (9.92 ml), in one portion. The resulting mixture was stirred at room temperature. After about 1 to 8 hours, the reaction was diluted with water (100 ml) and methylene chloride (100 ml). The organic phase was removed, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 14.4 g of oil.

Ίΐ NMR (CDCl ₃ ): δ 7.28 (d, 2H); 6.85 (d, 2H); 3.77 (s, 3H); 3.73 (s, 2H); 1.36 (s, 9H).

¹³ With NMR (CDCl ₃ ): δ 130, 114, 56, 35, 32.

Calculated for C ₁₂ H ₁₈ OS: C 68.52; H 8.63.

Found: C 68.80; H 8.67.

B. Preparation of Z-tert-butyl (4,4'-dimetho-stilbenyl) sulfide.

A solution of the compound obtained in example 2A (2.51 g) in tetrahydrofuran (50 ml) was cooled to about -20 ° C. The cold solution was treated with a solution of n-butyl lithium in hexane (1.6 M, 7.47 ml) for 10 minutes. The resulting solution was allowed to warm to about 0 ° C. over 35 minutes. The cold solution was treated with p-anisaldehyde (1.46 ml). After 1 to 5 minutes, the reaction solution was treated with methanesulfonyl chloride (0.95 ml). The resulting mixture was allowed to warm to room temperature. After 45 min, the reaction mixture was treated with a solution of tert-butoxide potassium in tetrahydrofuran (1.0 M, 12.0 ml). After another 45 minutes, the reaction was stopped by adding 1 N hydrochloric acid (12 ml). The organic phase was separated, dried over magnesium sulfate, filtered, and concentrated to an oil (4.4 g).

'H NMR (CDCl ₃ ): δ 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 With NMR (CDCl ₃ ): δ 153, 139, 137, 114, 56, 32.

C. Preparation of 2-tert-butyl (4,4'-dimethoxystilbenyl) sulfoxide.

The compound of example 2B was converted to the target compound by the method mainly described in example 1B.

^one H NMR (CDCl3): δ 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 C NMR (CDCl3): δ 142, 132.5, 131, 118, 117, 56, 24.

Calculated for C20H24O3S: C 69.74; H 7.02.

Found: C 69.98; H 6.94.

Example 3. E- and Z-tert-Butyl (4,4'-dimethoxystilbenyl) sulfoxide.

A. Preparation of tert-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-propanethiol (9.92 ml), in one portion. The resulting mixture was stirred at room temperature. After about 1 to 8 hours, the reaction was diluted with water (100 ml) and methylene chloride (100 ml). The organic phase was removed, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 14.4 g of oil.

^one H NMR (CDCl3): δ 7.28 (d, 2H); 6.85 (d, 2H); 3.77 (s, 3H); 3.73 (s, 2H); 1.36 (s, 9H).

¹³ With NMR (CDCl ₃ ): δ 130, 114, 56, 35, 32.

Calculated for C ₁₂ H ₁₈ OS: C 68.52; H 8.63.

Found: C 68.80; H 8.67.

B. Preparation of tert-butyl (4-methoxybenzyl) sulfoxide.

A solution of the compound obtained as described in Example 3A (14.4 g) in 1,2-dichloroethane (50 ml) was cooled to about 5 ° C and the cold solution was treated with peracetic acid (32% by weight in dilute acetic acid, 14.2 ml) within 30 min. After completing the addition of peracetic acid, the reaction mass was treated with a saturated solution of sodium chloride and sodium bicarbonate. The organic phase was removed, dried over magnesium sulfate, filtered, and concentrated to a yellow residue. The residue was treated with hexane (100 ml) and the resulting mixture was stirred at room temperature. After about 1 to 8 hours, the mixture was filtered and the solids were washed with hexane (100 ml). Drying the solid under vacuum gives 14.07 g of the title compound. Melting point 124-126 ° C.

^one H NMR (CDCl3): δ 7.26 (d, 2H): 6.89 (d, 2H); 3.79 (d, H); 3.78 (s, ZN); 3.58 (d, H); 1.3 (s, 9H).

¹³ C NMR (CDCl ₃ ): δ 132, 114, 56, 53, 23.

Calculated for C ₁₂ H ₁₈ O ₂ S: C 63.68; H 8.02.

Found: C 63.72; H 7.93.

C. Preparation of E- and Z-tert-butyl (4,4'-dimethoxystilbenyl) sulfoxide.

A solution of the compound obtained as described in Example 3B (10.0 g) in tetrahydro-furan (140 ml) was cooled to about -30 ° C to -25 ° C (dry ice / acetone bath). The cold solution was treated with n-butyl lithium 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 mixture was allowed to warm to about 20 ° C. The mixture was treated with methanesulfonyl chloride (3.5 ml). The reaction temperature rose from about 20 to about 35 ° C after the addition of methanesulfonyl chloride. The mixture was cooled to about 25 ° C and treated with a solution of potassium t-butoxide in tetrahydrofuran (1 M, 50.9 ml). After stirring for 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 spectra of carbon and proton NMR are similar to the spectra of the compound obtained in examples 1 and 2.

Example 4. E- and Z-Trimethylsilyl-4,4'dimethoxystilbenylsulfenate.

A mixture of the compound obtained as 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 h, the reaction mixture was allowed to cool to room temperature, filtered, and the filtrate was concentrated in vacuo to give the desired compounds as a mixture of regioisomers E / Z = 7: 1.

ISMT: m / z = 361 (M + 1). E-isomer:

^one H NMR ^ -benzene): δ 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). Z-isomer:

Ή-NMR D ₆ -benzene): δ 7.71 (d, 2H); 7.31 (d, 2H); 6.85 (d, 2H); 6.79 (d, 2H); 6.60 (s, 1H); 3.28 (s, 3N); 3.26 (s, 3H); -0.05 (s, 9H).

Example 5

E- and Z-Trimethylsilyl-4,4'-dimethoxystilbenylsulfenate.

A mixture of the compound obtained as described in Example 2 and 1,3-bis (trimethylsilyl) urea in toluene was heated to reflux. After 10 min, the mixture was allowed to cool, filtered, and concentrated in vacuo to obtain the desired compounds as a mixture of regioisomers E / Z = 7: 1.

E-isomer:

¹³ With NMR D ₆ -benzene. 8 ° C): δ 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 ZN.N-4n \ iCTH.i-4.4'-gn \ ictoxystilbenylsulfenamide.

A mixture of the compounds obtained as described in example 1.

(1.74 g) and 1,3-bis (trimethylsilyl) urea (578 mg) in toluene (54 ml) was heated under reflux. After 1.5 h, the reaction mixture was allowed to cool to room temperature and treated with dimethylamine (2.80 ml, 2.0 M solution in tetrahydrofuran). After two hours, the reaction solution was evaporated to dryness to obtain the target compounds as a mixture of regioisomers E / Z = 7: 1. This mixture was purified by flash chromatography on silica gel, eluent mixture ethyl acetate / hexane 9: 1, to give 1.06 g of the target compounds as mixtures of regioisomers E / Z = 8: 1.

ISMT: m / z = 315 (M +).

Calculated for Ci _eight H _2! NO ₂ S: C 68.54; H 6.71; N 4.44.

Found: C 68.40; H 6.69; N 4.22. E-isomer:

'll NMR ^ -benzene): δ 7.44 (d, 2H); 7.11 (d, 2H); 6.99 (s, 1H); 6.71 (d, 2H); 6.56 (d, 2H); 3.22 (s, 3N); 3.18 (s, 3H); 2.66 (s, 6H).

¹³ With NMR (d-benzene): δ 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.

Z-isomer:

^one H NMR (d-benzene): δ 7.61 (d, 4H); 6.82 (d, 2H); 6.80 (d, 2H); 6.80 (s, 1H); 3.32 (s, 3H); 3.27 (s, 3H); 2.41 (s, 6H).

¹³ With NMR ^ ₆ -benzene): δ 159.89, 159.30, 139.76, 136.46, 131.94, 131.82, 130.22, 130.20, 113.83, 113.76, 54.81.54 , 73, 48.61.

Example 7. E- and ZN, N-Dimethyl-4,4'-dimethoxystilbenylsulfenamide.

A mixture of the compound obtained as described in example 1 (1.74 g) and 1.3bis (trimethylsilyl) urea (578 mg) in toluene (54 ml) was boiled under reflux. After 1.5 h, the reaction mixture was allowed to cool to room temperature and treated with benzylamine (0.575 ml). After two hours, the reaction solution was evaporated to dryness to give the desired compounds as a mixture of regioisomers E / Z = 7: 1. The mixture was purified by flash chromatography on silica gel, eluant-mixture ethyl acetate / hexane 7: 1, to give 1.06 g of the desired compounds as a mixture of regioisomers E ^ = 6: 1.

Calculated for C ₂₃ H ₂₃ NO ₂ S: C 73.18; H 6.14; N 3.71.

Found: C, 73.16; H 6.18; N 3.50.

E-isomer:

ΊI NMR ^ -benzene): δ 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).

¹³ With NMR ^ ₆ -benzene): δ 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. Z-isomer:

ΊI NMR ^ -benzene): δ 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, 3N); 2.82 (t, 1H).

¹³ C NMR D ₆ -benzene): δ 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 (1.5 ml) and heated under reflux to remove water using a DinaStark nozzle. This boiling solution was treated with a solution of regioisomeric compounds, prepared as described in Example 4 (523 mg) in toluene (15 ml) for 15 minutes. After the addition was completed, an aliquot was taken for HPLC analysis. This analysis showed an in situ yield of the target compound of 46.6%.

Example 9. 6-Methoxy-2- (4-methoxyphenyl) benzo [b] thiophene.

A solution of p-toluenesulphonic acid monohydrate (1.26 g) in toluene (20 ml) was heated under reflux to remove water using a DinaStark nozzle. A solution of the regioisomeric compounds obtained as described in Example 6 (650 mg) in toluene (9 ml) was added to the boiling acid solution for 1.8 h. The reaction solution was treated with ethanol (10 ml) and the mixture was allowed to cool to room temperature. The resulting suspension 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 target compound. Melting point 199-200 ° C.

ΊI NMR (d ₆ -DMCO): δ 7.67 (d, 1H); 7.64 (d, 2H); 7.61 (s, 1H); 7.52 (d, 1H); 7.01 (d, 2H); 6.98 (dd, 1H); 3.81 (s, 3H); 3.79 (s, 3H).

Calculated from C 71.09; H 5.22.

Found: C 71.09; H 5.27.

Example 10. E- and Z-3- (4,4'-Dimethoxystilbenylthio) -6-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene.

A solution of p-toluenesulfonic acid monohydrate (552 mg) in toluene (111 ml) was heated under reflux to remove water using a Dean-Stark apparatus. A solution of the compound obtained as described in Example 1 (10 g) in toluene (34 ml) was added to a boiling acid solution over a period of six hours. After two hours, the mixture was cooled to 0 ° C. After 18 h, 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 27 solution. The organic phase was separated, dried with sodium sulfate, filtered, and concentrated in vacuo to give an orange oil. The oil was divided into two parts and each part was purified by flash chromatography, eluent hexane / ethyl acetate (3.5: 1). The fractions containing the target regioisomers were concentrated to an oil. The oil was treated with diethyl ether to selectively crystallize the regioisomer eluting first (155 mg). The mother liquor from these crystallization is enriched in the regioisomer, eluting the second. Isomer eluting first.

^one H NMR (CDCl ₃ ): δ 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, 3N); 3.66 (s, 3H).

High resolution MSBBA: calculated for C ₃₂ H ₂₉ OL (MH +) 541.1507.

Found: 541.1491.

Isomer eluting second.

'll NMR (CDCl ₃ ): δ 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 (s, 1H); 3.86 (s, 3H); 3.85 (s, 3N), 3.76 (s, 3H); 3.67 (s, 3H).

ISMT: m / z = 540 (m +).

Example 11. 6-Methoxy-2- (4-methoxyphenyl) benzo [b] thiophene.

The compound (isomer, eluting first), prepared as described in Example 1 0, (1 25 mg) was added to a boiling solution of p-toluenesulfonic acid monohydrate (4.2 mg) in toluene (1.5 ml). After six hours, methanesulfonic acid (7.5 ml) was added to the reaction mixture. After one hour, the reaction mixture was allowed to cool to room temperature. The resulting mixture was diluted with acetonitrile and analyzed by HPLC, which showed in situ the yield of the target compound was 71.1%.

Example 12. 1,2-Dichloroethane solvate of 6-hydroxy-2- (4-hydroxyphenyl) 3- [4- (2-piperidinoethoxy) benzoyl] benzo [b] thiophene hydrochloride.

A. Preparation of ethyl 4- (2-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 mixture was cooled to about 55 ° C and treated with additional 1- (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 / triethyl amine mixture (10: 6: 1, by volume) as eluent. Additional portions of 1- (2-chloroethyl) piperidine monohydrochloride were added until the initial 4-hydroxybenzoate was consumed. After completion of the reaction, 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 40 mm Hg. The resulting oil was used in the next step without further purification.

B. Preparation of 4- (2piperidinoethoxy) benzoic acid hydrochloride.

A solution of the compound obtained as described in Example 12A (about 13.87 g) in methanol (30 ml) was treated with 5N 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 5-10 ° C and concentrated hydrochloric acid (18 ml) was slowly added. The target compound crystallized during acidification. This crystalline product was collected by filtration and dried in vacuo at 40-50 ° C to obtain the target compound in 83% yield. Melting point 270271 ° C.

C. Preparation of 4- (2piperidinoethoxy) benzoyl chloride hydrochloride.

A solution of the compound obtained as in Example 12B (30.01 g) and dimethylformamide (2 ml) in methylene chloride (500 ml) was treated with oxalyl chloride (10.5 ml) for 30-35 minutes. After stirring for about 1 to 8 hours, the completeness of the reaction was analyzed by HPLC analysis. If the original carboxylic acid is present, additional oxalyl chloride may be added. After completion of the reaction, 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. The dissolve / evaporation procedure was repeated to obtain the desired 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 obtained as described in example 8 or 9, (2.92 g), the compound obtained as described in example 12C, (3.45 g) and 1,2-dichloroethane (52 mm) was cooled to about 0 ° C . Boron trichloride gas was condensed into a cold graduated cylinder (2.8 ml) and added to the cold mixture described above. After eight hours, the reaction mixture was treated at 0 ° C. with additional boron trichloride (2.8 ml). The resulting solution was heated at 35 ° C. After 16 h, the reaction was completed.

Methanol (30 ml) was treated with the reaction mixture obtained above for 20 minutes, which caused the methanol to boil. The resulting suspension 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 obtain 5.14 g of the target compound. Boiling point 225 ° C. Dilution rate (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) was heated under reflux and the water was removed using a Dean-Stark trap. A solution of the regioisomeric compounds obtained as described in Example 7 (780 mg) in toluene (9 ml) was added to the boiling acid solution over ten minutes. After one hour, the reaction solution was treated with ethanol (10 ml) and the resulting mixture was allowed to cool to room temperature. The resulting suspension was stirred at room temperature. After about 1 to 8 hours, the mixture was filtered to give 1 49 mg of the target compound. Melting point 199-200 ° C.

Calculated for Ci ₆ H ₁₄ O ₂ S: C 71.09; H 5.22.

Found: C, 71.05; H 5.22.

Example 14. E - and Z-4,4'-Dimethoxystilbetyl disulfide.

A solution of regioisomeric compounds prepared as described in Example 4 (1.83 g) in toluene (54 ml) was treated with ethanethiol (0.433 ml) and triethylamine (0.71 5 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 by chromatography on silica gel, eluting with ethyl acetate / hexane (9: 1) to obtain 1, 1 4 g of the target compounds as a mixture of regioisomers E ^ = 5.7: 1.

Calculated for C18H20O2S2: C 65.03; H 6.06.

Found: C, 65.32; H 6.28.

E-isomer:

^one H NMR ^ ₆ -benzene): δ 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).

¹³ With NMR ^ ₆ -benzene): δ 160.09, 159.16, 135.95, 131.71, 130.61, 130.16, 129.48, 126.88, 114.54, 113.99, 54.64, 54 61, 32.29, 14.33.

Z-isomer:

^one H NMR ^ ₆ -benzene): δ 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, 3H).

¹³ C NMR (d-benzene): δ 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 1 5. 6-Methoxy-2- (4-methoxyphenyl) benzo [b] thiophene.

A solution of p-toluenesulfonic acid monohydrate (1, 21 g) in toluene (20 ml) was heated under reflux and the water was removed using a Dean-Stark apparatus. A solution of the regioisomeric compounds obtained as described in Example 14 (685 mg, 5.7: 1 mixture of regioisomers) toluene (9 ml) was added to the boiling acid solution for 1.8 h. An aliquot of the mixture was analyzed by HPLC, which showed ib situ yield target compound 23.2%.

Claims (42)

SUMMARY OF THE INVENTION 1. A compound of the formula wherein R1 is hydrogen, C1-C4 alkoxy, arylalkoxy, halogen or an amino group; R2 is hydrogen, C1-C4 alkoxy, arylalkoxy, halogen or an amino group; R4 is OSi (R) 3, NR5R6 or SR8; each R independently represents C1-C6 alkyl, aryl or arylalkyl; R5 and R6 independently represent hydrogen, C1-C6 alkyl, arylalkyl or aryl, or R5 and R6 together with the nitrogen atom form a ring selected from piperidine, pyrrolidine, morpholine or hexamethylimine; and R8 is C1-C6 alkyl, aryl or arylalkyl. (1) the reaction of the compounds of formula II II in which R ₁ and R _{2 are} defined above, and R ₃ represents a thermally or acid-unstable C ₂ -C ₁₀ alkyl, C ₄ -C ₁₀ alkenyl or aryl (C ₁ -C ₁₀ ) alkyl; with a silylating reagent to obtain silyl sulfenates of formula IV in which R1 and R2 are as defined above; R7 is OSi (R) 3; and each R independently represents C ₁ -C ₆ alkyl, aryl or arylalkyl; and (2) reacting said silyl sulfenates with a mercaptan of formula HSR ₈ , wherein R _{8 is as} defined above, in the presence of an amine base. (1) the reaction of the compounds of formula II II in which R ₁ and R _{2 are} defined above, and R ₃ represents a thermally or acid-unstable C ₂ -C ₁₀ alkyl, C ₄ -C ₁₀ alkenyl or aryl (C ₁ -C ₁₀ ) alkyl; with a silylating reagent to obtain silyl sulfenates of formula IV in which R ₁ and R _{2 are as} defined above; R ₇ represents OSi (R) ₃ ; and each R independently represents C ₁ C6 alkyl, aryl or arylalkyl; and (2) the reaction of silyl sulfenates with an amine of the formula HNR5R6 in which R5 and R6 are as defined above. (1) the reaction of the compounds of formula II o II II in which R ₁ and R _{2 are} defined above, and R3 is a thermally or acid-unstable C ₂ -C ₁₀ alkyl, C ₄ -C ₁₀ alkenyl or aryl (C ₁ -C ₁₀ ) alkyl; with a silylating reagent to obtain silyl sulfenates of formula IV in which R ₁ and R _{2 are as} defined above; R ₇ represents OSi (R) ₃ ; and each R independently represents C ₁ -C ₆ alkyl, aryl or arylalkyl; (2) an optional reaction of silyl sulfenate with an amine of the formula HNR5R6 in which R5 and R _{6 are as} defined above; or (3) an optional reaction of a silyl sulfenate with a mercaptan of the formula HSR8 in which R8 is defined above in the presence of an amine base. 2. The compound according to claim 1, in which R ₁ represents hydrogen, C1-C4 alkoxy or arylalkoxy; and R ₂ represents hydrogen, a C ₁ -C ₄ alkoxy or an arylalkoxy group. 3. The compound according to claim 2, in which R represents OSi (R4) and each R independently represents Ci-CD alkyl, aryl or arylalkyl. 4. The compound according to claim 3, in which R4 is o-trimethylsilyl, o-triethylsilyl, otriisopropylsilyl, o-dimethylisopropylsilyl, o-diethylisopropylsilyl, o-dimethylhexylsilyl, o-tert-butyldimethylsilyl, o-tert-butyl-diphenyl-phenyl-diphenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl, butyl, phenylbenyl o-diphenylmethylsilyl or o-tert-butyldi (methoxyphenyl) silyl. 5. The compound according to claim 4, wherein R ₄ is o-trimethylsilyl, o-triethylsilyl, odimethylisopropylsilyl, o-diethylisopropylsilyl, o-tert-butyldimethylsilyl, o-tribenzylsilyl, o-triphenylsilyl. 6. The compound according to claim 5, in which R ₁ and R ₂ represent a CrQ alkoxy group. 7. The compound according to claim 6, in which R ₁ and R ₂ represent a methoxy group and R4 represents o-trimethylsilyl. 8. The compound according to claim 2, in which R ₄ represents NR5R6; and R5 and R6 independently represent hydrogen, ^ -Oz alkyl, arylalkyl or aryl, or R ₅ and R ₆ together with the nitrogen atom form a ring selected from piperidine, pyrrolidine, morpholine or hexamethylimine. 9. The compound of claim 8, in which R ₅ and R ₆ independently represent hydrogen, ^ - ^ - alkyl, arylalkyl, or R ₅ and R ₆ together with the nitrogen atom form a ring selected from piperidine and pyrrolidine. 10. The compound according to claim 9, in which R ₁ and R ₂ represent a QQ alkoxy group. 11. The compound of claim 10, in which R ₁ and R ₂ represent a methoxy group and R ₅ and R ₆ represent methyl. 12. The compound of claim 10, in which R ₁ and R ₂ represent a methoxy group, R5 represents hydrogen and R6 represents benzyl. 13. The compound according to claim 2, in which R ₄ represents SR ₈ and R ₈ represents C ₁ -C ₆ -alkyl, aryl or arylalkyl. 14. The compound of claim 13, wherein R ₈ is C1-C6 alkyl or arylalkyl. 15. The compound of claim 14, wherein R ₈ is C1-C6 alkyl. 16. The compound according to claim 1 to 5, in which R ₁ and R ₂ represent a C1-C4 alkoxy group. 17. The compound according to clause 16, in which R ₁ and R ₂ represent a methoxy group and R ₈ represents ethyl. 18. A method of obtaining a compound of formula III in which R ₁ represents hydrogen, C ₁ -C ₄ alkoxy, arylalkoxy, halogen or amino group ^p ; R2 is hydrogen, C1-C4 alkoxy, arylalkoxy, halogen or an amino group; R4 is OSi (R) 3, NR5R6 or SR8; each R, independently, is C ₁ C6 alkyl, aryl or arylalkyl; R ₅ and R ₆ independently represent hydrogen, C ₁ -C ₆ alkyl, arylalkyl or aryl, or R ₅ and R6 together with the nitrogen atom form a ring selected from piperidine, pyrrolidine, morpholine or hexamethylimine; and R8 is C1-C6 alkyl, aryl or arylalkyl; which includes: 19. The method according to p. 18 to obtain a compound of formula IV in which R ₁ represents hydrogen, C ₁ -C ₄ alkoxy, arylalkoxy, halogen or an amino group; R2 is hydrogen, C1-C4 alkoxy, arylalkoxy, halogen or an amino group; R7 is OSi (R) 3; each R, independently, is C ₁ C6 alkyl, aryl or arylalkyl, which includes a reaction of a compound of formula II o II II in which R1 and R2 are defined above, and R3 is a thermally or acid-unstable C ₂ -C ₁₀ alkyl, C ₄ -C ₁₀ alkenyl or aryl (C ₁ -C ₁₀ ) alkyl; with silylating reagent. 20. The method according to claim 19, in which R ₁ represents hydrogen, C1-C4 alkoxy or arylalkoxy; and R ₂ represents hydrogen, a C ₁ -C ₄ alkoxy or an arylalkoxy group. 21. The method according to claim 20, in which R ₇ is o-trimethylsilyl, o-triethylsilyl, otriisopropylsilyl, o-dimethylisopropylsilyl, o-diethylisopropylsilyl, o-dimethylhexylsilyl, o-tert-butyldimethylsilyl, o-tert-butyl-diphenyl-diphenyl triphenylsilyl, o-diphenylmethylsilyl or otretbutyl di (methoxyphenyl) silyl. 22. The method according to item 21, wherein the silylating reagent is bis (trialkylsilyl) urea or a combination of hexaalkyl disilylazane and a catalytic amount of trialkylsilyl chloride and R is C ₁ -O ₆ alkyl. 23. The method according to item 22, wherein the silylating reagent is bis (trimethylsilyl) urea and R is methyl. 24. The method according to item 23, in which R ₃ represents a thermally or acid-unstable C ₂ Sy-alkyl. 25. The method according to paragraph 24, in which Ri and R ₂ represent a methoxy group and R ₃ represents tert-butyl. 26. The method according to p. 18 of obtaining the compounds of formula V in which R ₁ represents hydrogen, C ₁ -C ₄ alkoxy, arylalkoxy, halogen or amino group ^p ; R2 is hydrogen, C1-C4 alkoxy, arylalkoxy, halogen or an amino group; and R ₅ and R ₆ independently represent hydrogen, C ₁ -C ₆ alkyl or aryl, or R ₅ and R ₆ together with the nitrogen atom form a ring selected from piperidine, pyrrolidine, morpholine or hexamethylimine, including: 27. The method of claim 26, wherein R ₁ is hydrogen, a C ₁ -C ₄ alkoxy or arylalkoxy group and R ₂ is hydrogen, a C ₁ -C ₄ alkoxy or arylalkoxy group. 28. The method according to item 27, wherein the silylating reagent is bis (trimethylsilyl) urea and R is methyl. 29. The method according to p, in which R ₃ represents a thermally or acid-unstable C2C10-alkyl. 30. The method according to clause 29, in which R ₁ and R ₂ represent a methoxy group and R3 represents tert-butyl. 31. The method according to clause 30, in which R ₅ and R ₆ independently represent hydrogen, C1-C6-alkyl or aryl. 32. The method according to p, in which R ₅ and R ₆ represent methyl or R ₅ represents hydrogen and R6 represents benzyl. 33. The method according to claim 1, 8 for producing a compound of formula XIV wherein R ₁ is hydrogen, C ₁ -C ₄ alkoxy, arylalkoxy, halogen or an amino group; R2 is hydrogen, C1-C4 alkoxy, arylalkoxy, halogen or an amino group; and R ₈ represents C ₁ -C ₆ alkyl, aryl or arylalkyl, which includes: 34. The method according to claim 33, wherein R ₁ is hydrogen, a C ₁ -C ₄ alkoxy or arylalkoxy group and R ₂ is hydrogen, a C ₁ -C ₄ alkoxy or arylalkoxy group. 35. The method according to clause 34, wherein the base of the amine is triethylamine, diisopropylethylamine or pyridine. 36. The method according to clause 35, wherein the silylating reagent is bis (trimethylsilyl) urea and R is methyl. 37. The method according to clause 36, in which R ₃ is thermally or acid-unstable C2C ₁₀ -alkyl. 38. The method according to clause 37, wherein the amine base is triethylamine. 39. The method according to § 38, in which R ₁ and R ₂ represents a methoxy group and R ₃ represents tert-butyl. 40. The method according to § 39, in which R ₈ represents a C ₁ -C ₆ -alkyl. 41. The method of claim 40, wherein R ₈ is ethyl. 42. A method of obtaining a compound of formula XIII in which R ₉ represents hydrogen, halogen, amino or hydroxy; R ₁₀ represents hydrogen, halogen, amino or hydroxy; R ₁₁ and R ₁₂ independently represent C ₁ -C ₄ alkyl, or R ₁₁ and R ₁₂ together with the adjacent nitrogen atom form a heterocyclic ring selected from piperidine, pyrrolidine, morpholine or hexamethylimine; and HX is NSh or NVg; which includes: (a) cyclization in the presence of an acid catalyst of a compound of formula III wherein R ₁ is hydrogen, C ₁ -C ₄ alkoxy, arylalkoxy, halogen or an amino group; R2 is hydrogen, C1-C4 alkoxy, arylalkoxy, halogen or an amino group; R ₄ represents OSi (R) ₃ , NR ₅ R ₆ or SR ₈ ; each R independently represents C ₁ -C ₆ alkyl, aryl or arylalkyl; R5 and R6 independently represent hydrogen, C ₁ -C ₆ alkyl or aryl, or R ₅ and R ₆ together with the nitrogen atom form a ring selected from piperidine, pyrrolidine, morpholine or hexamethylimine; and R ₈ represents C ₁ -C ₆ alkyl, aryl or arylalkyl; to obtain a benzothiophene compound of formula I in which R ₁ and R _{2 are as} defined above; (b) acylating said benzothiophene compound with an acylating reagent of formula XII XII in which R ₁₁ , R ₁₂ and HX are as previously defined; and R ₁₃ is chloro, bromo or hydroxy, in the presence of BX ' ₃ , in which X' is chloro or bromo; (c) if R ₁ and / or R ₂ represents a C ₁ -C ₄ alkoxy or arylalkoxy group, dealkylation of one or more phenolic groups of the acylation product of step (b) by reaction with an additional amount of BX ' ₃ , in which X' is defined above; and optionally (d) isolating a compound of formula XIII.