WO1995034550A1

WO1995034550A1 - Method of preparing benzothiophene derivatives

Info

Publication number: WO1995034550A1
Application number: PCT/EP1995/002138
Authority: WO
Inventors: Franz Kunisch; Lutz Heuer; Hermann Hagemann
Original assignee: Bayer Aktiengesellschaft
Priority date: 1994-06-16
Filing date: 1995-06-06
Publication date: 1995-12-21
Also published as: JPH10501542A; DE4420923A1; EP0765319A1; AU2737495A

Abstract

The invention concerns a method of preparing specially substituted benzothiophene derivatives of general formula (I) by reacting an appropriately substituted halobenzaldehyde with an anhydrous metal sulphides and/or metal hydrogen sulphides, followed by reaction with a 2-haloacetic acid ester.

Description

Process for the preparation of benzothiophene derivatives

The application relates to a process for the preparation of specially substituted benzthiophene derivatives of the general formula (I)

in which

R ^{1 represents} OR ³ , κι and optionally substituted C _r C ₁₂ alkyl,

wherein R ³ , R ⁴ and R ⁵ independently of one another represent hydrogen, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted aryl or aralkyl, and

R ^{2 represents} hydrogen, C _j -C ₆ alkyl, C _r C ₆ alkoxy, nitro or halogen.

The compounds are used as intermediates for the production of known pharmaceuticals, plant and material protection agents.

Ways of producing benzothiophene derivatives are known and are e.g. in EP 589 289, Tetrahedron Lett. 33, 7499 (1992), Tetrahedron 39, 4153 (1983), J.

Org. Chem. 37, 3224 (1972), US-5 169 961, EP 572 712, J. Chem. Soc. Perkin Trans. I, 1984. 385 and JP 05 155 881. JP 05 155 881 describes the preparation of benzothiophenes according to the following reaction scheme:

H, ONa, OK, OMe, OEt

However, the yields and purities claimed could not be achieved if the specified reaction conditions and the use of commercially available sodium hydrogen sulfide or sodium sulfide were observed.

In the trapping reaction of the 2-mercaptobenzaldehyde with 2-chloroacetoacetic acid derivatives, the sulfide also occurred as an undesirable secondary component

YOC s ^" COY on.

Surprisingly, it has now been found that the reaction of 2-halogen-substituted benzaldehyde (halogen = F, Cl, Br) with partially dehydrated sodium hydrogen sulfide or sodium sulfide leads to the desired 2-mercaptobenzaldehyde with higher yield and greater purity.

The application therefore relates to a process for the preparation of benzothiophene derivatives of the formula (I) by reacting compounds of the formula (II)

(II)

with a metal sulfide and / or metal hydrogen sulfide and subsequent reaction with compounds of the formula (III)

O

II (III)

^• R '

characterized in that dehydrated or at least partially dewatered metal sulfide and / or metal hydrogen sulfide is used for the reaction with the metal sulfide and / or metal hydrogen sulfide.

The compounds of formula (I) obtained in this way can then, if appropriate, also without intermediate isolation, i.e. in the form of a one-pot reaction to the known sulfones of the formula (Ia)

be oxidized.

Compounds in which

R ^{1 represents} OR, _ ^ .Ff ₅ and optionally substituted C _r C ₁₂ alkyl,

R and

R ³ , R ⁴ and R ⁵ independently of one another are hydrogen, straight-chain or branched alkyl having 1 to 12 carbon atoms, straight-chain or branched alkenyl having 2 to 12 carbon atoms or straight-chain or branched alkynyl having 2 to 12 carbon atoms, which given if substituted one to more times by halogen, furthermore for cycloalkyl having 3 to 12 carbon atoms, which is optionally substituted one or more times, identically or differently, by halogen or alkyl having 1 to 4 carbon atoms, furthermore for aryl which is optionally substituted one to five times by halogen, alkyl having 1 to 10 carbon atoms, haloalkyl with 1 to 8 carbon atoms and 1 to 8 identical or different halogen atoms, alkoxy with 1 to 10 carbon atoms, haloalkoxy with 1 to 8 carbon atoms and 1 to 8 identical or different halogen atoms, alkylthio with 1 to 10 carbon atoms , Haloalkylthio with 1 to 8 carbon atoms and 1 to 8 identical or different halogen atoms, amino, monoalkylamino with straight-chain or branched alkyl radicals with 1 to 6 carbon atoms, dialkylamino with identical or different, straight-chain or branched alkyl radicals with 1 to 6 carbon atoms each, cycloalkyl with 1 up to 6 carbon atoms, methylene dioxy, Di fluoromethylenedioxy, chlorofluoromethylenedioxy, dichloromethylenedioxy, nitro or cyano, furthermore for aralkyl, where the alkyl radical is straight or branched and consists of 1 to 8 carbon atoms and aryl preferably represents phenyl, which is optionally mono- to pentasubstituted by identical or different substituents by halogen, Alkyl with 1 to 6 carbon atoms, haloalkyl with 1 to 6 carbon atoms and 1 to 6 identical or different halogen atoms, alkoxy with 1 to 6 carbon atoms, haloalkoxy with 1 to 6 carbon atoms and 1 to 6 identical or different halogen atoms, alkylthio with 1 to 6 carbon atoms, haloalkylthio with 1 to 6 carbon atoms and 1 to 6 identical or different halogen atoms, amino, monoalkylamino with straight-chain and branched alkyl radicals with 1 to 6 carbon atoms, dialkylamino with identical or different, straight-chain or branched alkyl radicals with 1 to 6 carbon atoms each , Cycloalkyl with 1 to 6 Carbon atoms, methylenedioxy, difluoromethylenedioxy, chlorofluoromethylenedioxy, dichloromethylenedioxy, nitro or cyano, furthermore R ^{1 is} straight-chain or branched alkyl having 1 to 12 carbon atoms, which may be one or more identical or different by halogen, alkoxy having 1 to 6 Carbon atoms, acyl with 1 to 6 carbon atoms, acyloxy with 1 to 6 carbon atoms, (alkoxy) carbonyl with 1 to 6 carbon atoms, furthermore for cycloalkyl having 3 to 12 carbon atoms, which is optionally substituted one or more times, identically or differently, by halogen or

Alkyl with 1 to 4 carbon atoms, furthermore R ² for optionally one to five times substitution by hydrogen, straight-chain or branched alkyl with 1 to 6 carbon atoms, straight-chain or branched alkoxy with 1 to 6 carbon atoms, nitro or halogen.

Compounds of the formula (I) in which are very particularly preferred

R and optionally substituted C _r C ₁₂ alkyl,

and

R ³ , R ⁴ and R ⁵ independently of one another are hydrogen, straight-chain or branched alkyl having 1 to 8 carbon atoms, straight-chain or branched

Alkenyl with 2 to 8 carbon atoms or straight-chain or branched alkynyl with 2 to 6 carbon atoms, which is optionally substituted one to four times by halogen, furthermore for cycloalkyl with 3 to 8 carbon atoms, which is optionally substituted one to four times, identically or differently is, by halogen or

Alkyl with 1 to 4 carbon atoms, further for aryl, which is optionally mono- to tetrasubstituted by fluorine, chlorine, alkyl with 1 to 8 carbon atoms, haloalkyl with 1 to 6 carbon atoms and 1 to 6 fluorine and / or chlorine atoms, alkoxy with 1 to 8 carbon atoms, haloalkoxy with 1 to 6 carbon atoms and 1 to 6

Fluorine and / or chlorine atoms, alkylthio with 1 to 8 carbon atoms, haloalkylthio with 1 to 6 carbon atoms and 1 to 6 fluorine and / or chlorine atoms, amino, monoalkylamino with alkyl radicals of 1 to 4 carbon atoms, dialkylamino with the same or various alkyl radicals each having 1 to 4 carbon atoms, cycloalkyl having 1 to 6 carbon atoms, methylenedioxy, difluoromethylenedioxy, chlorofluoromethylenedioxy, dichloromethylenedioxy, nitro or cyano, furthermore for aralkyl, the alkyl radical being straight or branched and consisting of 1 to 8 carbon atoms and aryl for phenyl which is optionally mono- to tetrasubstituted by fluorine, chlorine, alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 4 carbon atoms and 1 to 4 fluorine and / or chlorine atoms, alkoxy with 1 to 4 carbon atoms, haloalkoxy with 1 to 4

Carbon atoms and 1 to 4 fluorine and / or chlorine atoms, alkylthio with 1 to 4 carbon atoms, haloalkylthio with 1 to 4 carbon atoms and 1 to 4 fluorine and / or chlorine atoms, amino, monoalkylamino with alkyl radicals of 1 to 4 carbon atoms, dialkylamino with the same or various alkyl radicals each having 1 to 4 carbon atoms, cycloalkyl having 1 to 6 carbon atoms, methylenedioxy, difluoromethylenedioxy, chlorofluoromethylenedioxy, dichloromethylenedioxy, nitro or cyano, furthermore R ^{1 is} straight-chain or branched alkyl having 1 to 8 carbon atoms, which, if appropriate one to more times, the same or different, by halogen, alkoxy having 1 to 3 carbon atoms, acyl having 1 to 3 carbon atoms, acyloxy having 1 to 3 carbon atoms (alkoxy) carbonyl having 1 to 3 carbon atoms, furthermore for cycloalkyl having 3 to 8 carbon atoms, which is optionally substituted once or twice, identically or differently, by halogen or alkyl with 1 to 4 carbon atoms, furthermore R ² for optionally one to five times substitution by hydrogen, straight-chain or branched alkyl with 1 to 4 carbon atoms, straight-chain or branched alkoxy with 1 to 4 carbon atoms, nitro or halogen,

Halogen stands for fluorine, chlorine, bromine and iodine.

Components (II) and (III) are commercially available or can be produced by known processes.

To dewater the metal sulfides and metal hydrogen sulfides, the metal sulfide is preferably sodium hydrogen sulfide, potassium hydrogen sulfide, sodium sulfide or potassium sulfide, but very particularly preferably sodium hydrogen sulfide and sodium sulfide, preferably in a solvent or a solvent mixture while distilling off the water contained in the metal sulfide. The following solvents can be used alone or as a mixture:

Hydrocarbons such as petroleum ether, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, hexane, cyclohexane and technical hydrocarbon mixtures, for example so-called white spirits with components with boiling points in the range from 40 to 250 ° C., ethers such as dipropyl and diisopropyl , Dibutyl, methyl t-butyl ether, tetrahydrofuran, 1,4-dioxane and polyether of ethylene oxide and / or propylene oxide, pyridine and tetramethylene ethylene diamine as well as dimethyl, dibutyl and ethylene carbonate, nitro compounds such as nitromethane, nitroethane, nitropropane and nitrobenzene, Nitriles such as acetonitrile, propionitrile and benzonitrile as well as compounds such as tetrahydrothiophene dioxide and dimethyl sulfoxide, tetramethylene sulfoxide, propyl sulfoxide, benzylmethyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, diisoamyl sulfoxide, polyether of ethylene oxide and / or propylene nitride, methyl nitride, and methyl nitride, Dimethyl-3,4,5,6-tetrahydro-2 (1H) pyrimidine, octyl pyrrolidone, octyl caprol actam, 1,3-dimethyl-2-imidazolinedione, dimethylformamide, dimethylacetamide, formamide, diethylformamide, N-formylpyrrolidine, N-formylmorpholine, N-formylpiperidine, N, N'-1,4-diformylpiperazine, dipropylformamide and dibutylformamide .

The following solvents are preferably used: benzene, toluene, xylene,

Chlorobenzene, dichlorobenzene, dimethyl sulfoxide, tetramethylene sulfoxide, N-methyl pyrrolidone, N methyl caprolactam, octyl pyrrolidone, octyl caprolactam, dimethyl formamide, 1,3-dimethyl-2-imidazolinedione, dimethylacetamide, formamide, dipropyl formamide and.

The following are very particularly preferred:

Toluene, xylene, chlorobenzene, dichlorobenzene, dimethyl sulfoxide, N-methylpyrrolidone, dimethylformamide, tetramethylene sulfoxide, 1,3-dimethyl-2-imidazolinedione and dimethylacetamide and mixtures of these solvents with one another.

The dewatering temperature can be varied within a wide range, ie between + 50 ° C and + 300 ° C, but preferably in the range from +100 to + 250 ° C. If necessary, an inert gas stream, preferably argon, helium or nitrogen, is introduced into the solution. The drainage time is 1 to 10 hours, preferably 1 to 5 hours.

The metal sulfide thus dewatered is then reacted with 2-halobenzaldehyde in which either 2-halobenzaldehyde, optionally diluted with one of the solvents listed, is added dropwise to the sulfide solution or the sulfide solution in the 2-halobenzaldehyde, optionally with a of the listed solvents is diluted, entered.

The reaction temperature for the conversion to 2-mercapto-benzaldehyde can be varied within a wide range; in general, the reaction is carried out at temperatures between + 25 ° C and + 200 ° C, preferably between + 50 ° C and + 150 ° C, most preferably between + 50 ° C and + 80 ° C. The reaction time is between 0.5 and 10 hours depending on the temperature.

The reaction with the reagent (LTI) is preferably carried out without isolation of the 2-mercaptobenzaldehyde formed by direct addition of the reagent (III) to the benzothiophene derivative of the formula (II), optionally with addition of a base and optionally with an increase in temperature, to the reaction obtained mixture.

The bases include inorganic bases such as sodium hydroxide solution, potassium hydroxide solution, sodium acetate and organic bases such as sodium methylate, sodium ethylate, potassium tert-butoxide, amidine or guanidine bases such as 1,5-diazabicyclo (4.3.0) non-5-ene (DBN), 1.8-

Diazabicyclo (5.4.0) undec-7-ene (DBU), N, N-dimethylaminopyridine, 1,4-diazabicyclo (2.2.2) octane (DABCO), trimethylamine, pyridine and N-methylmorpholine in question.

The alkylation of the 2-mercaptobenzaldehyde with the compound (III) and the subsequent cyclization can be carried out in a wide temperature range. In general, the reaction is carried out at temperatures from + 25 ° C to + 250 ° C, preferably from + 50 ° C and + 150 ° C. Depending on the temperature, the reaction time required is between 0.1 and 5 hours. The reaction products can be isolated in a conventional manner, ie either by filtering off or by extraction with organic solvents after aqueous work-up. If necessary, they can be purified in the usual way by crystallization, distillation, sublimation or chromatography.

Manufacturing example

21.4 g (0.16 mol) of sodium sulfide • 3H ₂ O are placed in 120 g of N-methylpyrrolidone (NMP) and 25 g of xylene. Over a period of about 3 hours, the xylene / water mixture is distilled off while simultaneously introducing nitrogen and finally at a final temperature of 195 ° C. NMP (total distillate about 90 g). After cooling to 80 ° C., the mixture is diluted with about 120 g of NMP and this solution is added dropwise at 60 ° C. to 15.2 g (0.11 mol) of 2-chlorobenzaldehyde in 50 g of NMP over about 30 minutes. The mixture is stirred at 60 ° C. for 30 minutes, 19.6 g (0.11 mol) of 2-chloro-cyclohexylacetamide in 35 g of NMP are added and the mixture is stirred for 5 minutes. After adding 9.6 g (0.11 mol) of 45% sodium hydroxide solution, stirring is continued at 60 ° C. for 10 minutes.

It is cooled to room temperature and the reaction mixture is poured into 2 liters of water. The precipitated crystal slurry is filtered off, washed with water and hexane and dried.

Yield: 20.1 g (content 80%, 58% corrected yield) of benzothiophene-2-cyclohexylcarbonamide

Claims

1. Process for the preparation of benzothiophene derivatives of the general formula (I)

in which

R ¹ for OR ³ , NT .R ^K 5 " ^unc * optionally substituted C _j -C ^ alkyl

stands,

R .7 ~ represents hydrogen, C _j -C ₆ alkyl, C _j -C ₆ alkoxy, nitro or halogen.

by reacting compounds of the formula (II)

in which

represents chlorine or bromine,

with a metal sulfide and / or metal hydrogen sulfide and subsequent reaction with compounds of the formula (III) O

II

.C. (HI)

2. The method according to claim 1, characterized in that compounds in which

R ¹ for OR ³ , and optionally substituted C _r C ₁₂ alkyl

stands, and

R ³ , R ⁴ and R ⁵ independently of one another are hydrogen, straight-chain or branched alkyl having 1 to 12 carbon atoms, straight-chain or branched alkenyl having 2 to 12 carbon atoms or straight-chain or branched alkynyl having 2 to 12 carbon atoms, which may be one to is substituted several times by halogen,

furthermore for cycloalkyl with 3 to 12 carbon atoms, which is optionally substituted one or more times, identically or differently, by halogen or alkyl having 1 to 4 carbon atoms, furthermore for aryl, which is optionally substituted one to five times by halogen, alkyl with 1 to 10 carbon atoms, haloalkyl having 1 to 8 carbon atoms and 1 to 8 identical or different

Halogen atoms, alkoxy with 1 to 10 carbon atoms, haloalkoxy with 1 to 8 carbon atoms and 1 to 8 identical or different halogen atoms, alkylthio with 1 to 10 carbon atoms, haloalkyl thio with 1 to 8 carbon atoms and 1 to 8 identical or different halogen atoms, Amino, monoalkylamino with straight-chain or branched alkyl radicals with 1 to 6 carbon atoms, dialkylamino with the same or different, straight-chain or branched alkyl- radicals with 1 to 6 carbon atoms each, cycloalkyl with 1 to 6 carbon atoms, methylenedioxy, difluoromethylenedioxy, chlorofluoromethylene dioxy, dichloromethylenedioxy, nitro or cyano, further for aralkyl, the alkyl radical being straight or branched and consisting of 1 to 8 carbon atoms and Aryl preferably represents phenyl which is optionally mono- to pentasubstituted, identical or different, by halogen, alkyl having 1 to 6 carbon atoms, haloalkyl having 1 to 6 carbon atoms and 1 to 6 identical or different halogen atoms, alkoxy having 1 to 6 Carbon atoms, haloalkoxy with 1 to 6 carbon atoms and 1 to 6 identical or different halogen atoms, alkylthio with 1 to 6 carbon atoms, haloalkylthio with 1 to 6 carbon atoms and 1 to 6 identical or different halogen atoms, amino, monoalkylamino with straight-chain and branched alkyl radicals with 1 to 6 carbon atoms, dialkylamino with the same or different straight, branched or branched

Alkyl radicals each having 1 to 6 carbon atoms, cycloalkyl having 1 to 6 carbon atoms, methylenedioxy, difluoromethylenedioxy, chlorofluoromethylenedioxy, dichloromethylenedioxy, nitro or cyano, furthermore R ^{1 is} straight-chain or branched alkyl having 1 to 12 carbon atoms, which may optionally be a up to several times the same or different by halogen, alkoxy having 1 to 6 carbon atoms, acyl having 1 to 6 carbon atoms, acyloxy having 1 to 6 carbon atoms, (alkoxy) carbonyl having 1 to 6 carbon atoms, furthermore for cycloalkyl having 3 to 12 carbon atoms, which optionally substituted one to more times, identically or differently, by halogen or alkyl having 1 to 4 carbon atoms, furthermore R ² for optionally one to five times substitution by hydrogen, straight-chain or branched alkyl having 1 to 6 carbon atoms, straight-chain or branched alkoxy with 1 to 6 carbon atoms, nitro or halogen.

3. The method according to claim 1, characterized in that sodium bisulfide, potassium hydrogen sulfide, sodium sulfide and / or potassium sulfide are used as the metal sulfides and metal hydrogen sulfides.

4. The method according to claim 1, characterized in that the reaction to 2-mercapto-benzaldehyde is carried out at temperatures from + 25 ° C to + 200 ° C.

5. The method according to claim 1, characterized in that the reaction with the reagent (III) without isolation of the 2-mercapto-benzaldehyde formed by direct addition of the reagent (III) to the benzothiophene derivative of the formula (II), optionally with the addition of a Base and optionally with an increase in temperature.

6. The method according to claim 5, characterized in that as the base inorganic bases such as sodium hydroxide solution, potassium hydroxide solution, sodium acetate and / or organic bases such as sodium methylate, sodium ethylate, potassium tert-butoxide, amidine or guanidine bases such as l, 5-diazabicyclo (4.3. 0) non-5-ene (DBN), 1,8-diazabicyclo (5.4.0) undec-7-ene (DBU), N, N-dimethylaminopyridine, 1,4-diazabicyclo (2.2.2) octane ( DABCO), trimethylamine, pyridine and N-methylmorpholine can be used.

7. The method according to claim 5, characterized in that the alkylation of the 2-mercaptobenzaldehyde with the compound (III) and the subsequent cyclization is carried out at temperatures from + 25 ° C to + 250 ° C.