WO1992017465A1 - Method of preparing 3-substituted thiophene - Google Patents

Method of preparing 3-substituted thiophene Download PDF

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Publication number
WO1992017465A1
WO1992017465A1 PCT/FI1992/000090 FI9200090W WO9217465A1 WO 1992017465 A1 WO1992017465 A1 WO 1992017465A1 FI 9200090 W FI9200090 W FI 9200090W WO 9217465 A1 WO9217465 A1 WO 9217465A1
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WIPO (PCT)
Prior art keywords
thiophene
preparing
reaction
formula
alkyl
Prior art date
Application number
PCT/FI1992/000090
Other languages
French (fr)
Inventor
Jan Näsman
Osmo Hormi
Anna-Liisa Tammi
Original Assignee
Neste Oy
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Publication date
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Publication of WO1992017465A1 publication Critical patent/WO1992017465A1/en

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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
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/08—Hydrogen atoms or radicals containing only hydrogen and carbon atoms

Definitions

  • the invention is concerned with a method of preparing 3-substituted thiophene with the following formula (I)
  • the derivatives of the thiophene are important raw materials in preparing different plastic products.
  • Thiophene is used as an intermediate for preparing such pharmaceuticals, especially antihistamines, that contain a thiophene part. It is also an intermediate in preparing veterinary pharmaceuticals, pesticides, dyes and so on.
  • Thiophene is advantageously prepared in laboratories so that anhydrous sodium succinate in powder form is heated together with phosphorus trisulfide to high tempratures in a flow of carbon dioxide.
  • the raw thiophene is condensed from the outcoming gas flow, it is steam-distilled and dried.
  • succinic acid anhydride is treated with phosphorus trisulfide or pentasulfide.
  • Sokony-vacuum (Mobil Oil Corporation) -method was based on a non- catalytic continuous reaction between butane and sulfur in high temperature.
  • SUBSTITUTE SHEET phase methods in which C 4 raw materials and sulfur sources are used, especially by means of metal oxide catalysts to avoid reaction speeds, yields and forming of thiophene tars.
  • a vapour phase reaction between furan and hydrogen sulfide is carried out by means of a metal oxide catalyst that contains heteropolyacid, as a result of which thiophene and water is achieved in a relatively low temperature (300-400°C).
  • the method can also be used to prepare 2-methyl-thiophene from 2-methyl furan and to prepare tetrahydrothiophene from tetrahydrofuran.
  • raw material as 1-butene, butadiene, n-butyl alcohol and croton aldehyde reacts continuously with carbon sulfide by means of a metal oxide catalyst that contain alkali in high temperatures (500°C).
  • carbon sulfide acts as a sulfur source, that apparently is converted to methane and carbon dioxide.
  • This method can also be used to prepare 2- and 3-alkyl substi- tuted thiophenes.
  • a continuous high temperature reaction (500-600°C) between butane and sulfur is carried out by means of a mixed metal oxide catalyst, that dehydrates the butane.
  • the hydrogen formed reacts quickly with sulfur to prepare hydrogen sulfide in a very exotermic reaction.
  • the hydrogen sulfide reacts with the butane rest to form thiophene with good yields.
  • 2- and 3-alkyl substituted thiophenes can be prepared from higher hydrogen carbons.
  • US Patent 3 939 179 is an example of the last-mentioned method and US Patent 3 822 289 is an example of the foregoing one.
  • the first-mentioned method is presented in US Patent 3 197 483.
  • thiophene is prepared by heating alkalisalts of succinic- or alkyl succinic acids in the temperature of 280-340°C with phosphorus sulfide (P0S5) by means of a hydrogen carbon with a high boiling point.
  • thiophenes are prepared by the reaction between alkyl succinic acid and their derivatives in the presence of phosphorus.
  • This invention is concerned with a new method of preparing 3-substituted thiophene by means of the reaction used in the publication mentioned Carpenter, AJ., Chadwick, DJ.; Journal of the Organic Chemistry.
  • R 1 and R 2 are alkyls
  • the reaction in the method there is first carried out as a first step the reaction known from said article after which the reaction is continued by strong acid to achieve the desired compound.
  • the advantages of the invention are that the amino group is removed from the product by using an one step reaction and that the reaction can be carried out preferably by acid and that a high temperature is not necess ⁇ ary. Only carbon oxide and a hydroxide of amine are achieved as by-product from which the amide can be recovered. In addition to that the starting materials are easily available compounds.
  • N-t-buthyl-2-thiophene amide 1,8 g (0,01 moles) was dissolved in 40 ml tetra- hydrofuran and cooled to -60°C. Nitrogen was used as protecting gas in the reaction. 0,02 moles of buthyl Utium was added to the hexane solution and the mixing was continued in the same temperature for 20 minutes. The heptyl bromide 1,8 g (0,01 moles) was dissolved in tetrahydrofuran and added to the cold mixture that could slowly warm up to room temperature. The protecting gas was removed and 40 ml of water was added to the mixture. The organic part of the solution was extracted separate with ether (3 x 60 ml).
  • N-t-buthyl-3-heptyl-2-thiophene amide was heated in a 20% hydro ⁇ gen chloride solution for ca 65 h to loose the amide group.
  • the organic com ⁇ pound was extracted with ether from the cooled solution, the solution was dried and the ether was evaporated.
  • the separated compound was 3-heptyl-thiophene with the boiling point of 247°C. Made with 50 mmol the yield received was 50%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (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)

Abstract

Method of preparing 3-substituted thiophene with formula (I) in which formula R1 is alkyl, by treating N-alkyl-3-alkyl-2-thiophene amide with a strong acid to loose the amide group and thus to get the compound of formula (I).

Description

Method of preparing 3-substituted thiophene
The invention is concerned with a method of preparing 3-substituted thiophene with the following formula (I)
Figure imgf000003_0001
in which formula R is alkyl.
The derivatives of the thiophene are important raw materials in preparing different plastic products.
Thiophene is used as an intermediate for preparing such pharmaceuticals, especially antihistamines, that contain a thiophene part. It is also an intermediate in preparing veterinary pharmaceuticals, pesticides, dyes and so on.
Thiophene is advantageously prepared in laboratories so that anhydrous sodium succinate in powder form is heated together with phosphorus trisulfide to high tempratures in a flow of carbon dioxide. The raw thiophene is condensed from the outcoming gas flow, it is steam-distilled and dried. Alternatively, succinic acid anhydride is treated with phosphorus trisulfide or pentasulfide. The previously known Sokony-vacuum (Mobil Oil Corporation) -method was based on a non- catalytic continuous reaction between butane and sulfur in high temperature.
Newer methods of preparing thiophene and its derivatives are continuous vapour
SUBSTITUTE SHEET phase methods in which C4 raw materials and sulfur sources are used, especially by means of metal oxide catalysts to avoid reaction speeds, yields and forming of thiophene tars. In one such a method a vapour phase reaction between furan and hydrogen sulfide is carried out by means of a metal oxide catalyst that contains heteropolyacid, as a result of which thiophene and water is achieved in a relatively low temperature (300-400°C). The method can also be used to prepare 2-methyl-thiophene from 2-methyl furan and to prepare tetrahydrothiophene from tetrahydrofuran.
In another method C. raw material, as 1-butene, butadiene, n-butyl alcohol and croton aldehyde reacts continuously with carbon sulfide by means of a metal oxide catalyst that contain alkali in high temperatures (500°C). Generally carbon sulfide acts as a sulfur source, that apparently is converted to methane and carbon dioxide. This method can also be used to prepare 2- and 3-alkyl substi- tuted thiophenes.
In a third method a continuous high temperature reaction (500-600°C) between butane and sulfur is carried out by means of a mixed metal oxide catalyst, that dehydrates the butane. The hydrogen formed reacts quickly with sulfur to prepare hydrogen sulfide in a very exotermic reaction. The hydrogen sulfide reacts with the butane rest to form thiophene with good yields. By this method 2- and 3-alkyl substituted thiophenes can be prepared from higher hydrogen carbons. US Patent 3 939 179 is an example of the last-mentioned method and US Patent 3 822 289 is an example of the foregoing one. The first-mentioned method is presented in US Patent 3 197 483.
The preparation of some derivatives of thiophene is known from the article Carpenter, A.J., Chadwick, D.J., Org. Chem 1985, 50, 4362 from which the follow¬ ing reaction is known:
Figure imgf000005_0001
2 n-HύLi/- lO', C/DMΞ, E"~ = clectrophil
.Another way of preparing the above mentioned same compound is known from the publication Tetrahedron Letters, Vol 26, No. 14, pp 1777-1780, 1985 in which thiophene carboxylic acid is litiated directly in 3-position. This reaction is, however, not as range selective as the reaction with carboxy amide and further¬ more it has to be carried out in a temperature of -78°C.
In the Japanese Patent Apphcation 50-154238 thiophene is prepared by heating alkalisalts of succinic- or alkyl succinic acids in the temperature of 280-340°C with phosphorus sulfide (P0S5) by means of a hydrogen carbon with a high boiling point.
In the Japanese Patent Application 51-006157 thiophenes are prepared by the reaction between alkyl succinic acid and their derivatives in the presence of phosphorus.
This invention is concerned with a new method of preparing 3-substituted thiophene by means of the reaction used in the publication mentioned Carpenter, AJ., Chadwick, DJ.; Journal of the Organic Chemistry.
The invention of preparing the compound of said formula I is thus mainly characterized in that N-alkyl-3-alkyl-2-thiophene amid of formula (II)
SUBSTITUTE SHEET
Figure imgf000006_0001
wherein R 1 and R 2 are alkyls,
is treated by strong acid to loose the amide group and to achieve the compound of formula (I).
In the method there is first carried out as a first step the reaction known from said article after which the reaction is continued by strong acid to achieve the desired compound. The advantages of the invention are that the amino group is removed from the product by using an one step reaction and that the reaction can be carried out preferably by acid and that a high temperature is not necess¬ ary. Only carbon oxide and a hydroxide of amine are achieved as by-product from which the amide can be recovered. In addition to that the starting materials are easily available compounds.
In the following we are describing the invention by means of an embodiment example from which the method of the invention appears in detail.
EMBODIMENT EXAMPLE
The preparation of 3-substituted thiophene from an amide of 2-thiophene carboxylic acid
Figure imgf000006_0002
SUBSTITUTE SHEET
Figure imgf000007_0001
N-t-buthyl-2-thiophene amide 1,8 g (0,01 moles) was dissolved in 40 ml tetra- hydrofuran and cooled to -60°C. Nitrogen was used as protecting gas in the reaction. 0,02 moles of buthyl Utium was added to the hexane solution and the mixing was continued in the same temperature for 20 minutes. The heptyl bromide 1,8 g (0,01 moles) was dissolved in tetrahydrofuran and added to the cold mixture that could slowly warm up to room temperature. The protecting gas was removed and 40 ml of water was added to the mixture. The organic part of the solution was extracted separate with ether (3 x 60 ml). The combined ether solutions were dried (NapSO ,) and the solution was evaporated. By dissolving the product in petrol ether and by crystallization in cold state' a major part of the contaminants could be removed by filtration. 2 g of N-t-buthyl-3-heptyl-2- thiophene amide was the result of the reaction which means a yield of 72%. Also non-wished side reactions could be noticed when the reaction temperature was -10°C.
When dimethoxy ethane is used as solvent the reaction is happened already in -10°C with a yield of 80%.
The obtained N-t-buthyl-3-heptyl-2-thiophene amide was heated in a 20% hydro¬ gen chloride solution for ca 65 h to loose the amide group. The organic com¬ pound was extracted with ether from the cooled solution, the solution was dried and the ether was evaporated. The separated compound was 3-heptyl-thiophene with the boiling point of 247°C. Made with 50 mmol the yield received was 50%.
The identification of the compound is presented in Enclosures 1-5.
SUBSTITUTE SHEET

Claims

Claims
1. Method of preparing 3-substituted thiophene with the following formula (I)
Figure imgf000008_0001
in which formula R is alkyl,
characterized in that N-alyl-3-alkyl-2-thiophene amide of formula (II)
Figure imgf000008_0002
wherein R 1 and R 2 are alkyls,
is treated with strong acid to loose the amide group and thus to get the com- pound of formula (I).
2. Method of Claim 1, characterized in that R 1 is heptyl or octyl and R 9 is t- butyl.
3. Method of Claim 1 or 2, characterized in that the strong acid is H SO ., HNOg, HCl, HBr, HF, H2P03, preferably HCl and the concentration of that in the range of 1-40%, preferably 20%.
SUBSTITUTE SHEET
4. Method of any of Claims 1-3, characterized in that the reaction is carried out in a low temperature, preferably 30-150°C..
PCT/FI1992/000090 1991-03-28 1992-03-26 Method of preparing 3-substituted thiophene WO1992017465A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FI911527 1991-03-28
FI911527A FI90540C (en) 1991-03-28 1991-03-28 Method for preparing 3-substituted thiophene

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5512685A (en) * 1991-12-09 1996-04-30 Neste Oy Process for the preparation of 3-substituted thiophenes

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0053603A1 (en) * 1980-11-28 1982-06-09 Laevosan-Gesellschaft m.b.H. & Co KG 1-(3-(2-Hydroxy-3-alkylaminopropoxy)-2-thienyl)-3-phenyl-1 propanones and their acid addition salts, and process for their preparation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0053603A1 (en) * 1980-11-28 1982-06-09 Laevosan-Gesellschaft m.b.H. & Co KG 1-(3-(2-Hydroxy-3-alkylaminopropoxy)-2-thienyl)-3-phenyl-1 propanones and their acid addition salts, and process for their preparation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J. AM. CHEM. SOC., Vol. 70, 1948, HARRY L. COONRADT et al., "The Chlorination of Thiophene. II. Substitution Products; Physical Properties of the Chlorothiophenes; the Mechanism of the Reaction", pp. 2564-2568. *
J. AM. CHEM. SOC., Vol. 95, No. 4, February 1973, BARRY M. TROST et al., "Reactions of Sulfuranes (Ylides) with Aromatic Carbonium Ions", pp. 1285-1294. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5512685A (en) * 1991-12-09 1996-04-30 Neste Oy Process for the preparation of 3-substituted thiophenes

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FI911527A0 (en) 1991-03-28
FI911527A (en) 1992-09-29
FI90540C (en) 1994-02-25
EP0577683A1 (en) 1994-01-12

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