DE3031738A1 - Benzothiophene derivs. prodn. - by cyclisation of 2-acyl-phenylthio-acetic acid cpds. using carboxylic acids e.g. propionic acid as condensation agent - Google Patents

Abstract

In a new process for the prodn. of benzo (b) thiophene derivs. (I), 2-(2-acyl-phenylthio)acetic acids (II) are cyclized at 50-200 deg.C in the presence of carboxylic acids as condensation agents and opt. in the presence of inert organic solvents (where R1 is H or an unbranched, branched or cyclic, saturated or unsaturated aliphatic hydrocarbon residue the chain of which is opt. interrupted by O or S and which is opt. substd. by cycloalkyl, halogen, NO2, alkoxy, OH, phenyl or pyridyl, R1 is aryl, aralkyl or thienyl, furyl or pyridyl, the aryl or heteroaryl residue opt. carrying 1-3 identical or different substituents selected from alkyl, alkenyl, alkoxy, halogen, CF3, OCF3, NO2, amino and OH; R2 is H, NO2, hydroxyamino or NR'2"; and R' and R" are H, alkyl, alkenyl, aralkyl, aryl, formyl, carbonylalkyl, carbonylaralkyl, carbonylaryl, carbamoyl, thiocarbamoyl, alkylsulphonyl, aralkylsulphonyl, arylsulphonyl, alkoxycarbonyl or aryloxycarbonyl, the alkyl, aralkyl and aryl residues opt. being substd. by alkyl, cycloalkyl, phenyl, halogen, CF3, OCF3, alkoxy, acyl or NO2). Also new is the use of cpds. (I) in which R2 is NO2 in the prodn. of 7,8,9,10-tetrahydro-thieno/3,2-e/ pyrido/4,3-b/indoles by reduction of the NO2 group to an amino or hydrazino group by conventional methods.

Description

Process for the production of benzoithiophene derivatives

Vaten and Their Use as Intermediate Products The present invention relates to a new, chemically peculiar ring closure process for the production of partially known Benzoli7thiophene derivatives and their use as intermediates in the manufacture of biologically active compounds.

It has already become known that benzo [b] thiophenes can be reacted of ortho-halobenzaldehydes, ortho-haloacetophenones or ortho-halobenzophenones with thioglycolic acid esters under the action of alkalis into corresponding benzot / thiophene-2-carboxylic acid esters can convert that in an aqueous alkaline medium to the corresponding BenzoLi7thiophene-2-carboxylic acids saponified and then under the usual conditions at high temperature in Quinoline can be decarboxylated in the presence of copper powder (cf. e.g.

N.B. Chapman, K. Clarke and S.N. Sawhney, J. Chem. Soc.

(C) 1968, 518; M. Martin-Smith, W.E. Snaeder, J. Brown and S.T. Reid, J. Chem. Soc. (C) 1967, 1899). It has also become known that 2-acylphenylthio) acetic acids in the presence of alkalis or under the action cyclized by strong acids to the corresponding renzoi7thiophene-2-carboxylic acids can be made from which by subsequent decarboxylation in quinoline with copper powder the benzobathiophenes are accessible (cf. e.g. C. Angelini, Ann. Chim. (Rome) 47, 705 (1957); C.A. 52, 1136 i (1958). - C. Finzi, C. Angelini and G. Grandolini, Ann. Chim. (Rome) 45, 54 (1955); C. A.

50, 4968h (1956). - D. Walker and J. Reib, J Org. Chem.

28, 3077 (1963)).

The invention relates to a process for the preparation of some known benzoLbJthiophene derivatives of the general formula (I), in which R1 is hydrogen or a straight-chain, branched or cyclic, saturated or unsaturated aliphatic hydrocarbon radical which is optionally interrupted in the chain by oxygen or sulfur and which is optionally substituted by cycloalkyl, halogen, nitro, alkoxy, hydroxy, phenyl or Pyridyl, or an aryl or aralkyl radical or a heteroaryl radical from the group thienyl, furyl or pyridyl, the aryl radical or the heteroaryl radical optionally having 1 to 3 identical or different substituents from the group alkyl, alkenyl, alkoxy, halogen, trifluoromethyl, Trifluoromethoxy, nitro, amino or hydroxy and R2 represents hydrogen, nitro, hydroxyamino or the group N (R ') (R "), where R' and R" are identical or different and each represent hydrogen, alkyl, alkenyl, aralkyl , Aryl, formyl, carbonylalkyl, carbonylaralkyl or carbonylaryl, carbamoyl or thiocarbamoyl, alkylsulfonyl, aralkylsulfonyl, aryl sulfonyl, alkoxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl, the alkyl, aralkyl and aryl radicals mentioned being optionally substituted by alkyl, cycloalkyl, phenyl, halogen, trifluoromethyl, trifluoromethoxy, alkoxy, acyl or nitro, characterized in that (2-acylphenylthio ) acetic acids of the general formula (II) in which R1 and R2 have the sedeutang specified under formula (I), cyclized in the presence of carboxylic acids as condensation media and optionally in the presence of inert organic solvents at temperatures between 50 and 2000C.

It is advantageous to use the carboxylic acids used as condensing agents to be used as a solvent and diluent at the same time. As carboxylic acids are preferably mentioned: aliphatic carboxylic acids of the general composition CnH2n + 1 COOH (n = 1 to 20), especially acetic acid, propionic acids, butyric acid, Isobutyric acid and the higher homologues with up to 20 carbon atoms; cycloaliphatic Carboxylic acids of the general composition CnH2n ICOOH (n = 5 to 7), in particular Cyclopentanecarboxylic acid, cyclohexanecarboxylic acid or cycloheptanecarboxylic acids as well aryl-substituted representatives of the aliphatic carboxylic acids such as phenylacetic acid or phenylpropionic acid, as well as mixtures of these carboxylic acids.

The use of propionic acid has proven to be particularly advantageous proven.

The reaction temperatures can be varied within a relatively wide range will. In general, temperatures between 500 ° C. and 1800 ° C. are preferred in the range from 1100C to 1500C.

The reaction can take place in an inert atmosphere at normal pressure, but also can be carried out at increased pressure. In general, normal pressure is used under protective gas such as nitrogen or argon.

When carrying out the process according to the invention, the (2-acylphenylthio) acetic acid derivative is used of the formula II dissolved in the condensing agent and until the evolution of carbon dioxide has ended heated. The substances according to the invention are preferably isolated and purified in such a way that, after insoluble substances have been separated off, the condensing agent is removed in vacuo distilled off and the product obtained in crystalline form from a suitable solvent recrystallized.

It is extremely surprising that according to the invention Process the benzoLithiophene derivatives of the general formula (I) in such good yields and in high purity from the (2-acylphenylthio) acetic acids of the general formula (II) can be obtained because one had to expect in view of the state of the art, that the benzogthiophenes unsubstituted on carbon atom 2 among those described Reaction conditions either not at all or only in very poor yields directly are to be obtained. When using the strongly acidic condensing agents known from the literature arise the 2-carboxy-benzoLi7thiophen-Derivate, which so far in an additional Reaction step decarboxylated under very drastic reaction conditions will must (see e.g. B. Iddon and R.M. bcrowston in "Advances in Heterocyclic Chemistry", Jol. 11: R-cent Advances in the Chemistry of BenzotbJt-aiophenes (Ed .: A.R. Katritzky and A.J. Boulton), pp. 177-381. Academic Press, New York and London, 1970).

The method according to the invention has a number of advantages. In comparison to the previously known method, there is no isolation and purification des 2-carboxybenzogb7thiophens, the difficult-to-control decarboxylation reaction in the melt or in high-boiling bases at temperatures around 2000C in the presence of copper powder and the formation of by-products that are difficult to remove. Farther one reaction stage is saved and the yield of those unsubstituted in the 2-position is saved BenzoLi7thioPhenen is significantly higher than according to the previously known methods.

Of particular interest is the inventive production of Compounds of the general formula (I), in which R1 stands for hydrogen, straight-chain, branched or cyclic alkyl with up to 8 carbon atoms, which optionally interrupted by an oxygen or sulfur atom in the chain and / or which is substituted by cyclic alkyl with 3 to 7, preferably with 5 to 6 ring members, by halogen, in particular by a or several fluorine, chlorine or bromine atoms, by alkoxy with 1 to 4, preferably with 1 to 2 carbon atoms, represented by phenyl or pyridyl or a phenyl radical, optionally by one or two identical or different substituents the group halogen, nitro, trifluoromethyl, trifluoromethoxy, alkyl or alkoxy with is substituted in each case by 1 to 4, in particular by 1 to 2 carbon atoms, R2 represents hydrogen, nitro, hydroxyamino or the group N (R ') R "), where R' and R "are identical or different and each represent hydrogen, straight-chain, branched or cyclic alkyl or alkenyl with up to 8 carbon atoms, where the alkyl chain is optionally substituted by phenyl or halogen, or for Formyl, carbonylalkyl or alkylsulfonyl having 1 to 8, in particular 1 to 4, carbon atoms stand, where the alkyl radicals mentioned are optionally substituted by phenyl or halogen, in particular one or more fluorine atoms, or for carbonylphenyl or phenylsulfonyl, the phenyl radical in turn substituted can be by halogen, preferably fluorine or chlorine, or by trifluoromethyl, Nitro, acyl, alkyl or alkoxy each having 1 to 4, in particular 1 to 2 carbon atoms, or are carbamoyl or thiocarbamoyl, the nitrogen atoms of which are substituted can be through phenyl or alkyl radicals, with 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, the alkyl radicals on the nitrogen atom optionally via a heteroatom from the group consisting of oxygen, sulfur or via an NH, N-alkyl, N-acyl or N-alkoxycarbonyl group closed to form a 4- to 8-membered ring can be, or for phenyloxycarbonyl or alkoxycarbonyl with up to 6 carbon atoms stand, the alkoxy radical optionally being substituted by phenyl, halophenyl or nitrophenyl is substituted.

Particular emphasis should be given to compounds prepared according to the invention of general formula (I) in which R1 for hydrogen or straight-chain or branched or cyclic alkyl with up to 8 carbon atoms stands, which is optionally substituted by phenyl, fluorine, chlorine, pyridyl, Alkoxy with 1 to 4 carbon atoms or cycloalkyl with 5 to 6 ring members, or stands for a phenyl radical which is optionally replaced by fluorine, chlorine, nitro, trifluoromethyl or trifluoromethoxy is substituted and R2 is a substituent in the 5-position which is hydrogen, nitro, hydroxyamino or the group N (R ') (R "), where R 'and R "are identical or different and each represent hydrogen or straight-chain or branched alkyl having 1 to 4 carbon atoms, the alkyl radical is optionally substituted by phenyl, chlorine or fluorine or for formyl, Carbonylalkyl, carbonylphenyl, alkylsulfonyl or phenylsulfonyl, where the mentioned alkyl radicals contain 1 to 4 carbon atoms and wherein the alkyl radicals and the phenyl radicals are optionally substituted by fluorine, chlorine, phenyl, Trifluoromethyl, nitro, acetyl, alkyl or alkoxy each with 1 to 2 carbon atoms, or for carbamoyl or thlocarbamoyl, the nitrogen atom is a nitrogen atom is optionally substituted by phenyl or alkyl with 1 to 4 carbon atoms, and wherein the alkyl radicals together with the nitrogen atom optionally a 5- to 8-membered ring, which is a white heteroatom from the group oxygen, May contain sulfur, NH or N-alkyl, or for phenyloxycarbonyl or alkoxy carbonyl with up to 6 carbon atoms, the alkoxy radical optionally through Phenyl, halophenyl or nitrophenyl is substituted.

In addition to the preparation examples listed below, the following benzogi7thiophene derivatives which can be prepared according to the invention are called: 5-ureidobenzothiophene, 5- (3-methylureido) benzothiophene, 5- (3-phenylureido) benzothiophene, 3-methyl-5-acetylaminobenzothiophene, 3-methyl-5- (4-chlorobenzoylamino) benzothiophene, 3-methyl-5-benzylaminobenzothiophene, 3-methyl-5-formylaminobenzothiophene, 3-methyl-5-phenyloxycarbonylaminobenzothiophene, 3 -Methyl-5- (4-methylphenylsulfonyl) aminobenzothiophene, 3-ethyl-5-ethoxycarbonylaminobenzothiophene, 3-ethyl-5-trifluoroacetylaminobenzothiophene, 3-ethyl-5-methylsulfonylaminobenzothiophene, 3-phenyl-5- (3, 3-diethylureido) benzothiophene, 3-phenyl-5- (piperidinocarbonylamino) benzothiophene, 3-phenyl-5- (morpholinocarbonylamino) benzothiophene, 3-cyclohexlyethyl-5-nitrobenzothiophene, 3-cyclohexylethyl-5-benzylcarbonylaminobenzothiophene.

In the process according to the invention, the benzo-Lh7 thiophene-1) derivatives of the general formula (I) in smooth reaction, excellent yield and high Maintain purity. The method according to the invention is thus an asset of technology.

The compounds of the general formula prepared according to the invention (I) represent valuable intermediates for the synthesis of biologically active ingredients, in particular of active pharmaceutical ingredients. For example, from the compounds in which R² stands for a nitro group by reducing the corresponding amino or hydrazine compounds, which in turn u 7,8,9,10-tetrahydrothieno [3,2-e] pyrido [4,3-b] indoles can be unset (cf. DT-OS 2 854 014).

The pharmaceutical active ingredients produced in this way have, among other things beneficial effects on the central nervous system.

The (2-acylphenylthio) acetic acids which can be used according to the invention general formula (II) are known or can be prepared by methods known from the literature produced worth the (cf.e.g. C. Finzi, C. Angelini and G. Grandolini, Ann. Chim. (Rome) 45, 54 (1955); C.A. 50, 4968h (1956).

- A. Ricci and N. Cagnoli, Ann. Chim. (Rome) 45, 172 (1955); C. A. 50, 5564c (1956). - C. Angelini, Ann.

Chim. (Rome), 47, 705 (1957); C.A. 52, 1136 i (1958). -S. Middleton, Austral. J. Chem. 12, 218 (1959)).

The following examples are given to illustrate the process according to the invention: Example 1 3-Methyl-5-nitrobenzothiophene 3.5 mol of (2-acetyl-4-nitrophenylthio) acetic acid are poured over the reaction flask with 3.5 liters of propionic acid, the mixture is heated to the boil and the resulting solution is boiled under the reflux condenser for 9 to 10 hours until the evolution of carbon dioxide has ended.

When the reaction has ended, the propionic acid is distilled off, the crystalline one The residue was taken up in 3 liters of dichloromethane and the solution with aqueous potassium hydrogen carbonate solution washed. Then it is filtered through a 3 cm thick aluminum oxide layer, the filtrate evaporates to dryness and recrystallizes from isopropanol.

Yield: 92% of theory; M.p. 118-1190C.

In analogy to Example 1, the following BenzoLiJ-thiophenes were prepared from the corresponding (2-acyl-5-nitrophenylthio) acetic acids: Example 2 5-Nitrobenzothiophene Condensing agent: propionic acid / phenylacetic acid (1: 1) Yield: 68% of theory. Example 3 3-Ethyl-5-nitrobenzothiophene Condensing agent: propionic acid Yield: 86% of theory. Example 4 3-Butyl-5-nitrobenzothiophene Condensing agent: cyclohexanecarboxylic acid Yield: 72% of theory. Example 5 3-Isopentyl-5-nitrobenzothiophene Condensing agent 3-phenylpropionic acid Yield: 70% of theory Example 6 3-phenethyl-5-nitrobenzothiophene Condensing agent: heptanoic acid Yield: 72% of theory Example 7 3-Phenyl-5-nitrobenzothiophene Condensation agent: propionic acid Yield: 85% of theory

Claims (7)

Patent claim 41 /. Process for the preparation of Benzolfl7thiophene derivatives of the general formula (I) in which R1 is hydrogen or a straight-chain, branched or cyclic, saturated or unsaturated aliphatic hydrocarbon radical which is optionally interrupted in the chain by oxygen or sulfur and which is optionally substituted by cycloalkyl, halogen, nitro, alkoxy, hydroxy, phenyl or Pyridyl, or an aryl or aralkyl radical or a heteroaryl radical from the group thienyl, furyl or pyridyl, the aryl radical or the heteroaryl radical optionally having 1 to 3 identical or different substituents from the group alkyl, alkenyl, alkoxy, halogen, trifluoromethyl, Contain trifluoromethoxy, nitro, amino or hydroxy and R2 represents hydrogen, nitro, hydroxyamino or the group N (R ') R "), where R' and R" are identical or different and each represent hydrogen, alkyl, alkenyl, aralkyl, Aryl, formyl, carbonylalkyl, carbonylaralkyl or carbonylaryl, carbamoyl or thiocarbamoyl, alkylsulfonyl, aralkylsulfonyl, arylsu Ifonyl, alkoxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl, the alkyl, aralkyl and aryl radicals mentioned are optionally substituted by alkyl, cycloalkyl, phenyl, halogen, trifluoromethyl, trifluoromethoxy, alkoxy, acyl or nitro, characterized in that (2-acylphenylthio ) acetic acids of the general formula (II) in which R1 and R2 have the meaning given under formula (I), in the presence of carboxylic acids as condensing agents and optionally in the presence of inert organic solvents at temperatures between 50 and 200 ° (cyclized. 2. Process for the preparation of compounds of the general formula (I) according to claim 1, in which R1 is hydrogen, straight-chain, branched or cyclic alkyl with up to 8 carbon atoms, which optionally is interrupted by an oxygen or sulfur atom in the chain and / or which is substituted by cyclic alkyl with 3 to 7, preferably: e with 5 bí; 6 ring links, by halogen, in particular dL ch e or more fluorine, chlorine oser bromate c e, by alkoxy with 1 to 4, preferably with 1 to 2 carbon atoms, by phenyl (the pyridy or stands for a phenyl radical, dec if necessary by an or two identical or different substituents from the group halogen, nitro, trifluoromethyl, Trifluoromethoxy, alkyl or alkoxy, each with 1 to 4, in particular with 1 to 2 Carbon atoms is substituted, R2 for hydrogen, nitro, hydroxyamino or the group N (R ') R "), where R' and R" are identical or different and are each represents hydrogen, straight-chain, branched or cyclic alkyl or alkenyl with up to 8 carbon atoms, the alkyl chain optionally being substituted by phenyl or halogen is substituted, or for formyl, carbonylalkyl or Alkylsulfonyl having 1 to 8, in particular 1 to 4 carbon atoms, where the alkyl radicals mentioned are optionally substituted by phenyl or halogen, in particular one or more fluorine atoms, or for carbonylphenyl or phenylsulfonyl stand, it being possible for the phenyl radical in turn to be substituted by halogen, preferably Fluorine or chlorine, or by trifluoromethyl, nitro, acyl, alkyl or alkoxy with in each case 1 to 4, in particular 1 to 2 carbon atoms, or for carbamoyl or Thiocarbamoyl, the nitrogen atoms of which can be substituted by phenyl or alkyl radicals, with 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, where the alkyl radicals on the nitrogen atom optionally via a heteroatom from Group oxygen, sulfur or via an NH, N-alkyl, N-acyl or N-alkoxycarbonyl group can be closed to form a 4- to 8-membered ring, or for phenyloxycarbonyl or alkoxycarbonyl with up to 6 carbon atoms, the alkoxy radical is optionally substituted by phenyl, halophenyl or nitrophenyl. 3, Process for the preparation of compounds of the general formula (I) according to claim 1, in which R1 is hydrogen or straight-chain or branched or cyclic alkyl with up to 8 carbon atoms stands which, if applicable is substituted by phenyl, fluorine, chlorine, pyridyl, alkoxy having 1 to 4 carbon atoms or cycloalkyl with 5 to 6 ring members, or represents a phenyl radical, which optionally is substituted by fluorine, chlorine, nitro, trifluoromethyl or trifluoromethoxy and R2 stands for a substituent in the 5-position which is hydrogen, nitro, hydroxyamino or denotes the group N (R ') (R "), where R' and R '" are identical or different and each represents hydrogen or straight-chain or branched alkyl with 1 to 4 carbon atoms, the alkyl radical optionally being substituted by phenyl, chlorine or fluorine is substituted or for formyl, carbonylalkyl, carbonylphenyl, alkylsulfonyl or phenylsulfonyl, said alkyl radicals having 1 to 4 carbon atoms contain and where the alkyl radicals and the phenyl radicals are optionally substituted are due to fluorine, chlorine, Phenyl, trifluoromethyl, nitro, acetyl, Alkyl or alkoxy each having 1 to 2 carbon atoms, or for carbamoyl or Thiocarbamoyl, where the nitrogen atom is optionally substituted by Phenyl or alkyl of 1 to 4 carbon atoms, and where. die.Alkylreste together with the nitrogen atom optionally one 5- to 8-membered ring, which has another heteroatom from the group oxygen, May contain sulfur, NH or N-alkyl, or for phenyloxycarbonyl or alkoxycarbonyl with up to 6 carbon atoms, the alkoxy radical optionally through Phenyl, halophenyl or nitrophenyl is substituted. 4. Process for the preparation of compounds of the general formula (I) according to claim 1, characterized in that the reaction is carried out at temperatures Performs between SOOC and 1800C. 5. The method according to claim 4, characterized in that as Condensing agents aliphatic carboxylic acids with up to 20 carbon atoms are used. 6. The method according to claim 4, characterized in that as Condensation agent propionic acid is used. 7. Use of compounds of general formula (I) in which R2 stands for a nitro group in the production of 7,8,9,10-tetrahydrothieno [3,2-e] -1 pyrido [4,3-b] indoles, characterized in that these compounds are used reduced by conventional methods to amino or hydrazine compounds.