WO1995034548A2 - Procede de preparation de derives de benzothiophene - Google Patents

Procede de preparation de derives de benzothiophene Download PDF

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Publication number
WO1995034548A2
WO1995034548A2 PCT/EP1995/002136 EP9502136W WO9534548A2 WO 1995034548 A2 WO1995034548 A2 WO 1995034548A2 EP 9502136 W EP9502136 W EP 9502136W WO 9534548 A2 WO9534548 A2 WO 9534548A2
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WIPO (PCT)
Prior art keywords
carbon atoms
atoms
straight
different halogen
different
Prior art date
Application number
PCT/EP1995/002136
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German (de)
English (en)
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WO1995034548A3 (fr
Inventor
Hermann Uhr
Original Assignee
Bayer Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Priority to AU27373/95A priority Critical patent/AU2737395A/en
Publication of WO1995034548A2 publication Critical patent/WO1995034548A2/fr
Publication of WO1995034548A3 publication Critical patent/WO1995034548A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2

Definitions

  • the application relates to a new process for the preparation of benzothiophene-2-carboxylic acid esters and amides.
  • methyl benzothiophene-2-carboxylate can be prepared by reacting o-nitrobenzaldehyde and methyl mercaptoacetate in the presence of a base. (see also J.R Beck, J. Org. Chem. 37; 3224 (1972)).
  • o-Nitrobenzaldehyde is a relatively expensive educt, which is only accessible through complex syntheses, and the space-time yields are extremely unfavorable.
  • Li salt of fluorobenzene moving with dimethylformamide and reacting the resulting o-fluorobenzaldehyde with methyl mercaptoacetate in the presence of base, methyl benzothiophene-2-carboxylate is obtained (see also EP 0 568 289).
  • Lithium alkyls require very low temperatures during implementation and, because of their flammability, require expensive safety technology.
  • R 1 represents -OR ö or N ,.
  • R 6 , R 7 and R 8 independently of one another represent hydrogen, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl,
  • R 2 , R 3 , R 4 and R 5 each independently represent hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, dialkylamino, nitro or cyano,
  • R, R, R, R and R have the meaning given above, first reacted with diazotization reagents and then reacted with substances which are suitable for exchanging a diazonium group for hydrogen.
  • benzothiophene-2-carboxylic acid esters and amides can be prepared in a smooth reaction by the process according to the invention, since it was not previously known from the prior art that benzothiophene derivatives which have an amino group in the thiophene part included, can be implemented by diazotization.
  • the method according to the invention is characterized by a number of advantages.
  • the required starting substances and also the reaction components are thus accessible in a simple manner and also in large quantities.
  • the implementation of the implementation and the isolation of the desired substances pose no problems.
  • the process according to the invention enables the production of benzothiophene-2-carboxylic acid esters and amides in high yield and good purity.
  • Formula (II) provides a general definition of the 3-amino-benzothiophene-2-carboxylic acid esters and amides required as starting materials when carrying out the process according to the invention.
  • R preferably represents -OR or _
  • R R 6 , R 7 and R 8 independently of one another preferably represent hydrogen, straight-chain or branched alkyl having 1 to 18 carbon atoms, straight-chain or branched alkenyl having 2 to 18 carbon atoms or straight-chain or branched alkynyl having 2 to 18 carbon atoms, which may be one to is substituted several times the same or different by halogen, alkoxy having 1 to 6 carbon atoms, haloalkoxy having 1 to 6 carbon atoms and 1 to 9 identical or different halogen atoms, alkylthio having 1 to 6 carbon atoms, haloalkylthio having 1 to 6 carbon atoms and 1 to 9 identical or different halogen atoms, acyl with 1 to 6 carbon atoms, acyloxy with 1 to 6 carbon atoms, (alkoxy) carbonyl with 1 to 6 carbon atoms in the alkoxy part, amino, which is optionally substituted identically or differently by alkyl or aryl, optionally substitute
  • Carbon atoms which are optionally substituted one or more times, identically or differently, by halogen, alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 4 carbon atoms and 1 to 5 identical or different halogen atoms, alkoxy having 1 to 4 carbon atoms, haloalkoxy having 1 to 4 coblene atoms and 1 to
  • alkylthio with 1 to 4 carbon atoms alkylthio with 1 to 4 carbon atoms, haloalkylthio with 1 to 4 carbon atoms and 1 to 5 identical or different halogen atoms, nitro or cyano, furthermore for aryl, which is optionally substituted one to five times by halogen, alkyl with 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 10 carbon atoms, haloalkylthio with 1 to 8
  • R 2 , R 3 , R 4 and R 5 each independently of one another preferably represent hydrogen, halogen, alkyl having 1 to 6 carbon atoms, haloalkyl having 1 to 6 carbon atoms and 1 to 6 identical or different halogen atoms,
  • R 1 particularly preferably represents -OR 6 or
  • R 6 , R 7 and R 8 independently of one another are particularly preferably
  • alkyl radical straight or branched and consisting of 1 to 8 carbon atoms and aryl for phenyl, which is optionally substituted one to four times is with fluorine, chlorine, alkyl
  • 1 to 4 carbon atoms haloalkyl with 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 different alkyl radicals each with 1 to 4 carbon atoms, cycloalkyl with 1 to 6 carbon atoms, methylenedioxy, difluoromethylenedioxy, chlorofluoromethylenedioxy, dichloromethylenedioxy, nitro or cyano.
  • R 2 , R 3 , R 4 and R 5 each independently of one another particularly preferably represent hydrogen, chlorine, fluorine, alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 4 carbon atoms and 1 to 6 fluorine and / or chlorine atoms, alkoxy 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms and 1 to 6 fluorine and / or chlorine atoms, alkylthio with
  • the diazonium salt is generally not isolated, but is immediately reacted further. However, isolation of the diazonium salt, for example in the case of the diazonium fluoroborates, is also possible.
  • the diazotization of 3-aminobenzothiophene-carboxylic acid esters and amides of the general formula (II) is generally carried out in acidic, aqueous solution which optionally cosolvents are added, carried out by reaction with sodium nitrite.
  • the sodium nitrite is generally added dropwise as an aqueous solution to an acidic solution, suspension or emulsion of 3-aminobenzothiophene-carboxylic acid esters or amides of the general formula (II).
  • the nitrite solution can also be introduced and the solution of the 3-aminobenzothiophene carboxylic acid ester or amide (II) can be added dropwise.
  • Mineral acids as well as organic acids, and mixtures of one or more acids can be used to prepare the acidic solutions.
  • Hydrochloric acid, sulfuric acid, phosphoric acid are preferably suitable as mineral acids; formic acid, acetic acid, trifluoroacetic acid are preferably used as organic acids.
  • concentration of the acids can be varied within a very wide range, in general they are 5 to 95%.
  • the reaction temperature for diazonium salt formation can be varied within a wide range. In general, temperatures between -20 ° C and 50 ° C, preferably at -10 ° C to 25 ° C.
  • nitrites such as methyl nitrite, ethyl nitrite, propyl nitrite, iso-propyl nitrite, butyl nitrite, sec-butyl nitrite, iso-butyl nitrite, tert-butyl nitrite, or benzyl nitrite, or isopentyl nitrite are used.
  • the process is carried out in aqueous or organic solutions, which may be acidified by adding mineral acids or organic acids. All customary solvents can be used as organic solvents in this process.
  • Hydrocarbons such as benzene, toluene or hexane, halogenated hydrocarbons such as carbon tetrachloride, chloroform, methylene chloride, ethers such as diethyl ether, dipropylene ether, dibutyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, 1,3-dioxlan, glycol dimethyl ether are preferably usable.
  • Alcohols such as methanol, ethanol, propanol, iso-propanol, butanol, tert-butanol, also dimethylformamide, acetonitrile, hexamethylphosphoric acid amide, nitromethane, dimethyl sulfoxide.
  • the acids that can optionally be added are either mineral acids or organic acids or mixtures of different acids.
  • Hydrochloric acid, sulfuric acid, phosphoric acid, borofluorohydric acid are preferably used as mineral acids; formic acid, acetic acid, trifluoroacetic acid are preferably used as organic acids.
  • the reaction temperatures can be varied within a very wide range and are between -20 ° C and + 100 ° C depending on the solvent.
  • the second sub-step replacement of the diazonium salt residue for hydrogen
  • the solvents required for this reaction already serve as a hydrogen source.
  • the solutions as described above or the isolated diazonium salt are then reacted with reagents which can exchange the diazonium salt group for hydrogen.
  • reagents which can exchange the diazonium salt group for hydrogen.
  • H 3 PO 2 solutions metals, triethylsilane or metal salts, preferably iron, zinc, tin, copper, Cu (I) salts such as Cu 2 O, CuCl, Cu 2 SO 4 or complex hydrides, preferably Sodium or potassium borohydride, LiAlH 4 , tributyltin hydride, or reaction is carried out directly with hydrogen gas, if appropriate in the presence of catalysts, preferably Raney nickel, Raney cobalt, palladium or platinum on various supports, such as, for example, carbon, barium sulfate. This can be done under pressure or without pressure.
  • Organic aldehydes in alkaline solution can also serve as reducing agents.
  • reaction temperature for this substep can be varied over a wide range. Generally one works between -20 ° C and 100 ° C, preferably between -10 ° C and 50 ° C.
  • the solvents used for this step correspond to those used in the preparation of the diazonium salts (if the diazonium salts are not be isolated). If the diazonium salt has been isolated, it is also possible to work in aqueous solution and / or organic solvents which may have been acidified by organic acids or mineral acids. In some cases it is also necessary to work in alkaline solutions.
  • All customary solvents can be used as organic solvents in this process.
  • Hydrocarbons such as benzene, toluene or hexane, halogenated hydrocarbons such as carbon tetrachloride, chloroform, methylene chloride, ethers such as diethyl ether, dipropylene ether, di-butyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, 1,3-dioxolane, are preferably usable.
  • Glycol dimethyl ether alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, and also dimethylformamide, acetonitrile, hexamethylphosphoric acid amide, nitromethane, dimethyl sulfoxide.
  • alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, and also dimethylformamide, acetonitrile, hexamethylphosphoric acid amide, nitromethane, dimethyl sulfoxide.
  • reaction products are isolated in the usual way, either by filtering off or by extraction with organic solvents. If necessary, they can be purified in the usual way by crystallization, distillation, sublimation or chromatography.
  • the benzothiophene-2-carboxylic acid esters and amides obtained serve as starting materials in the production of urokinase inhibitors (EP 0 568 289) and fungicides (EP 0 512 349).
  • R 2 , R 3 , R 4 , R 5 , R 7 and R 8 have the meanings described above alternatively also obtained if one has in this case arisen during the reaction Benzothiopen-2-carboxylic acid esters of the general formula (I), where R 1 is -OR 6 and R 2 , R 3 , R 4 , R 5 and R 6 have the meaning described above with amines of the general formula (III)
  • This reaction step can be carried out either with or without a solvent.
  • the 3-amino-benzothiophene-2-carboxylic acid esters or amides of the general formula (II) which can be used as starting materials are known or can be prepared by known processes (see: JR Beck, J. Org. Chem. 37, 3224 (1972 ); Coppola, Gary M .; J. Heterocycl. Chem., 19, 717 (1982); U.S. Patent 3,755,583; DE-OS 2,165,962).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Selon un procédé nouveau de préparation d'esters et d'amides d'acide carboxylique de benzothiophène-2 ayant la formule (I), dans laquelle R?1, R2, R3, R4 et R5¿ ont la signification donnée dans la description, on fait premièrement réagir des esters ou des amides d'acide carboxylique de 3-amino-benzothiophène-2 ayant la formule (II), dans laquelle R?1, R2, R3, R4 et R5¿ ont la signification donnée dans la description, avec des réactifs diazotants puis avec des substances capables de remplacer un groupe diazonium par hydrogène.
PCT/EP1995/002136 1994-06-16 1995-06-06 Procede de preparation de derives de benzothiophene WO1995034548A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU27373/95A AU2737395A (en) 1994-06-16 1995-06-06 Process for preparing benzothiophene derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4420922.3 1994-06-16
DE19944420922 DE4420922A1 (de) 1994-06-16 1994-06-16 Verfahren zur Herstellung von Benzothiophenderivaten

Publications (2)

Publication Number Publication Date
WO1995034548A2 true WO1995034548A2 (fr) 1995-12-21
WO1995034548A3 WO1995034548A3 (fr) 1996-02-08

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DE (1) DE4420922A1 (fr)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7329764B2 (en) 2003-07-31 2008-02-12 Boehringer Ingelheim Pharmaceuticals, Inc. Substitute benzothiophene compounds
US7405225B2 (en) 2002-06-06 2008-07-29 Boehringer Ingelheim Pharmaceuticals, Inc. Substituted 3-amino-thieno[2,3-b]pyridine-2-carboxylic acid amide compounds and processes for preparing and their uses
US7592353B2 (en) 2006-06-06 2009-09-22 Boehringer Ingelheim International Gmbh Substituted 3-amino-thieno[2,3-b]pyridine-2-carboxylic acid amide compounds and processes for preparing and their uses

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4055556A (en) * 1973-09-06 1977-10-25 Sandoz Ltd. Monoazo and disazo compounds having optionally further substituted 2-acyl-, carboxy- or cyano-benzothienyl diazo component radicals

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4055556A (en) * 1973-09-06 1977-10-25 Sandoz Ltd. Monoazo and disazo compounds having optionally further substituted 2-acyl-, carboxy- or cyano-benzothienyl diazo component radicals

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
S. GRONOWITZ 'The Chemistry of Heterocyclic Compounds: Thiophene and its Derivatives' 1987 , JOHN WILEY AND SONS , NEW YORK * pages 670-671, 675-677 * *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7405225B2 (en) 2002-06-06 2008-07-29 Boehringer Ingelheim Pharmaceuticals, Inc. Substituted 3-amino-thieno[2,3-b]pyridine-2-carboxylic acid amide compounds and processes for preparing and their uses
US7329764B2 (en) 2003-07-31 2008-02-12 Boehringer Ingelheim Pharmaceuticals, Inc. Substitute benzothiophene compounds
US7592353B2 (en) 2006-06-06 2009-09-22 Boehringer Ingelheim International Gmbh Substituted 3-amino-thieno[2,3-b]pyridine-2-carboxylic acid amide compounds and processes for preparing and their uses

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Publication number Publication date
WO1995034548A3 (fr) 1996-02-08
DE4420922A1 (de) 1995-12-21
AU2737395A (en) 1996-01-05

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