CA1055509A - Process for the preparation of 2-(2-thienyl)-ethylamine and derivatives thereof - Google Patents
Process for the preparation of 2-(2-thienyl)-ethylamine and derivatives thereofInfo
- Publication number
- CA1055509A CA1055509A CA245,047A CA245047A CA1055509A CA 1055509 A CA1055509 A CA 1055509A CA 245047 A CA245047 A CA 245047A CA 1055509 A CA1055509 A CA 1055509A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- derivative
- thienyl
- preparation
- ethylamine
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired
Links
Classifications
-
- 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
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
Abstract
Process for the preparation of 2 (2-thienyl)-ethylamine and derivatives thereof ABSTRACT OF THE DISCLOSURE
This invention relates to a process for the preparation of compounds of the formula:
(I) in which R1 and R2 may represent hydrogen or a lower alkyl or optionally substituted phenyl radical, comprising aminating a derivative of the formula:
This invention relates to a process for the preparation of compounds of the formula:
(I) in which R1 and R2 may represent hydrogen or a lower alkyl or optionally substituted phenyl radical, comprising aminating a derivative of the formula:
Description
This invention relates to a new process for the preparation of 2-(2-thienyl)-ethylamine and derivatives thereof, which are known compounds used as intermediates in the synthesis of a large number of derivatives used in both the chemical and pharmaceutical industries.
The compounds prepared according to the process of this invention have the following general formula:
Rl ~ CH - CH - NH2 (I) in which Rl and R2 each represent hydrogen or a lower alkyl or an optionally substituted phenyl radical. They have already been prepared according to a variety of methods. Thus, their synthesis was effected by reduction of 2-~-nitrovinyl-thiophene with lithium aluminum hydride (S. Gronovitz & F. Sandberg, Arkiv. for Kemi, 1970, 32, 217; M.L. Dressler, M. Soullié, J. Het. Chem., 1970, 7, 1257).
They have also been prepared from 2-(2-thienyl)-propylamide, by means of a Hoffman degradation reaction (G. Barger, A. Easson, J. Chem. Soc., 1938, 2100).
Other authors have also operated by reduction of 2-cyanomethyl-thiophene with lithium aluminum hydride (B.F.
Crowe, F.F. Nord, J. Org. Chem., 1950, 15, 8I; J.W. MacFarland, H.L. Howes, J. Med. Chem., 1969, 12, 1079).
However, such prior methods are, all three, diffi-cultly applicable industrially and do not provide compounds of the formula (I) in good yields.
Consequently, the object of the present invention is to provide an inexpensive industrial synthesis process which will produce 2-(2-thienyl)-ethylamine and derivatives thereof of the aforementioned formula (I) in good yields.
,~
The process according to this invention comprises aminating a derivative of the formula:
R~
~CH - CH - S03R3 ( I I ) in which Rl and R2 are as defined for formula (I), and in which R3 is an optionally substituted alkyl, aryl or aralkyl group, such as CH3, CCl 3, CF3, p CH3-C6H4 ~
According to an embodiment of the process of this invention, the amination is carried out directly by reacting the derivative of the formula (II) with ammonia.
10The reaction is generally conducted in the hot, in an autoclave, during a period of time of 10-20 hours.
According to another embodiment of the process of this invention, the derivative of the formula (II) is reacted with phthalimide, to give a compound having the formula:
¢~CH - CH - N~ J3 (III) `
which is subsequently transaminated with an amine or hydrazine hydrate.
As amine, use is made of a markedly basic mono- or poly-functional amine of high boiling point. Typically useful amines have the formula RNH2 in which R may be a C8-C25 straight or branched chain alkyl radical, an aralkyl radical (typically benzylamine and its substituted derivatives), an aryl radical such as an optionally substituted phenyl or naphthyl radical, particularly the halogeno-anilines, the alkyloxyanilines and benzidine. The radical R itself may carry other NH or NH2 functions, as in bis(2-amino-ethyl)amine (diethylenetriamine), ethylenediamine, triethylenetetramine, or even other functional groups such as hydroxy, ester, alkoxy, and the like. Thus, the amine may be 4-hydroxy-butylamine,
The compounds prepared according to the process of this invention have the following general formula:
Rl ~ CH - CH - NH2 (I) in which Rl and R2 each represent hydrogen or a lower alkyl or an optionally substituted phenyl radical. They have already been prepared according to a variety of methods. Thus, their synthesis was effected by reduction of 2-~-nitrovinyl-thiophene with lithium aluminum hydride (S. Gronovitz & F. Sandberg, Arkiv. for Kemi, 1970, 32, 217; M.L. Dressler, M. Soullié, J. Het. Chem., 1970, 7, 1257).
They have also been prepared from 2-(2-thienyl)-propylamide, by means of a Hoffman degradation reaction (G. Barger, A. Easson, J. Chem. Soc., 1938, 2100).
Other authors have also operated by reduction of 2-cyanomethyl-thiophene with lithium aluminum hydride (B.F.
Crowe, F.F. Nord, J. Org. Chem., 1950, 15, 8I; J.W. MacFarland, H.L. Howes, J. Med. Chem., 1969, 12, 1079).
However, such prior methods are, all three, diffi-cultly applicable industrially and do not provide compounds of the formula (I) in good yields.
Consequently, the object of the present invention is to provide an inexpensive industrial synthesis process which will produce 2-(2-thienyl)-ethylamine and derivatives thereof of the aforementioned formula (I) in good yields.
,~
The process according to this invention comprises aminating a derivative of the formula:
R~
~CH - CH - S03R3 ( I I ) in which Rl and R2 are as defined for formula (I), and in which R3 is an optionally substituted alkyl, aryl or aralkyl group, such as CH3, CCl 3, CF3, p CH3-C6H4 ~
According to an embodiment of the process of this invention, the amination is carried out directly by reacting the derivative of the formula (II) with ammonia.
10The reaction is generally conducted in the hot, in an autoclave, during a period of time of 10-20 hours.
According to another embodiment of the process of this invention, the derivative of the formula (II) is reacted with phthalimide, to give a compound having the formula:
¢~CH - CH - N~ J3 (III) `
which is subsequently transaminated with an amine or hydrazine hydrate.
As amine, use is made of a markedly basic mono- or poly-functional amine of high boiling point. Typically useful amines have the formula RNH2 in which R may be a C8-C25 straight or branched chain alkyl radical, an aralkyl radical (typically benzylamine and its substituted derivatives), an aryl radical such as an optionally substituted phenyl or naphthyl radical, particularly the halogeno-anilines, the alkyloxyanilines and benzidine. The radical R itself may carry other NH or NH2 functions, as in bis(2-amino-ethyl)amine (diethylenetriamine), ethylenediamine, triethylenetetramine, or even other functional groups such as hydroxy, ester, alkoxy, and the like. Thus, the amine may be 4-hydroxy-butylamine,
2-pentoxy-propylamine, ethanolamine, and the like.
The reaction is preferably effected in the hot, and diethylenetriamine, benzylamine or ethanolamine are advan-tageously used.
The reaction of the derivative of the formula (II) with phthalimide is usually carried out in the presence of an inorganic or organic base, such as an alkali metal (Na, K) or alkaline-earth metal (Ca) carbonate or hydroxide, an alkali metal (Na, K) amine, an alkali metal (Na) hydride, an alkali metal alkoxide, and the like.
The following non-limiting examples are given to illustrate the invention.
Preparation of 2-amino-1-(2-thienyl)propane, via direct amination Into a 1000 ml autoclave, are added 1-(2-thienyl)-2-propanol p-toluenesulfonate (75 9) and ammonia (600 ml). The whole is heated to 80C during 15 hours. After cooling, the autoclave is opened and the ammonia is allowed to evaporate.
After adding water (100 ml) and a lN sodium hydroxide solution (175 ml), the resulting material is extracted with ether. The ether phase is separated and then mixed with lN hydrochloric acid (75 ml). The aqueous phase is made alkaline and is then extracted with ether. The ether extract is washed with a 5%
sodium bicarbonate solution, and then with a saturated sodium chloride solution, after which it is dried over sodium sulfate.
After evaporation, the residue is distilled i~ va~uo, to give 19 9 2-amino-1-(2-thienyl)-propane (Yield: 53%) boiling at 84-86C under 12 mm Hg.
EXAMPLE 2Preparation of 2-(2-thienyl)-ethylamine, via indirect amination a) Preparation of N-2-(2-thienyl)-ethyl phthalimide To a solution maintained at 80C and comprising 294 9 (2 moles) phthalimide dissolved in 800 ml dimethylformamide, are added 120 9 anhydrous sodium carbonate followed, within 1.25 hour, by a solution of 564 9 (2 moles) 2-(2-thienyl)-ethyl paratoluenesulfonate in 20 ml dimethylformamide. The reaction medium is maintained at 80C during 2 hours and 20 minutes and is then cooled and poured over 1 litre water.
The resulting precipitate is collected by filtration, it is then washed, dried and recrystallized from ethanol, to give 396 9 N-2-(2-thienyl)-ethyl phthalimide (Yield: 44%) which has a melting point (Koefler block) of 129-130C.
b) Preparation of 2-(2-thienyl)-ethylamine 51.4 9 (0.2 mole) of the N-2-(2-thienyl)-ethyl phthalimide are mixed with 10.3 g diethylenetriamine (0.1 mole) and heated at 120C during 4 hours. The pressure is then gradually decreased to 19 Torr, and distillation gives 19.7 9 2-(2-thienyl)-ethylamine (Yield: 77%) which has a boiling point of 98C/l9 Torr.
The reaction is preferably effected in the hot, and diethylenetriamine, benzylamine or ethanolamine are advan-tageously used.
The reaction of the derivative of the formula (II) with phthalimide is usually carried out in the presence of an inorganic or organic base, such as an alkali metal (Na, K) or alkaline-earth metal (Ca) carbonate or hydroxide, an alkali metal (Na, K) amine, an alkali metal (Na) hydride, an alkali metal alkoxide, and the like.
The following non-limiting examples are given to illustrate the invention.
Preparation of 2-amino-1-(2-thienyl)propane, via direct amination Into a 1000 ml autoclave, are added 1-(2-thienyl)-2-propanol p-toluenesulfonate (75 9) and ammonia (600 ml). The whole is heated to 80C during 15 hours. After cooling, the autoclave is opened and the ammonia is allowed to evaporate.
After adding water (100 ml) and a lN sodium hydroxide solution (175 ml), the resulting material is extracted with ether. The ether phase is separated and then mixed with lN hydrochloric acid (75 ml). The aqueous phase is made alkaline and is then extracted with ether. The ether extract is washed with a 5%
sodium bicarbonate solution, and then with a saturated sodium chloride solution, after which it is dried over sodium sulfate.
After evaporation, the residue is distilled i~ va~uo, to give 19 9 2-amino-1-(2-thienyl)-propane (Yield: 53%) boiling at 84-86C under 12 mm Hg.
EXAMPLE 2Preparation of 2-(2-thienyl)-ethylamine, via indirect amination a) Preparation of N-2-(2-thienyl)-ethyl phthalimide To a solution maintained at 80C and comprising 294 9 (2 moles) phthalimide dissolved in 800 ml dimethylformamide, are added 120 9 anhydrous sodium carbonate followed, within 1.25 hour, by a solution of 564 9 (2 moles) 2-(2-thienyl)-ethyl paratoluenesulfonate in 20 ml dimethylformamide. The reaction medium is maintained at 80C during 2 hours and 20 minutes and is then cooled and poured over 1 litre water.
The resulting precipitate is collected by filtration, it is then washed, dried and recrystallized from ethanol, to give 396 9 N-2-(2-thienyl)-ethyl phthalimide (Yield: 44%) which has a melting point (Koefler block) of 129-130C.
b) Preparation of 2-(2-thienyl)-ethylamine 51.4 9 (0.2 mole) of the N-2-(2-thienyl)-ethyl phthalimide are mixed with 10.3 g diethylenetriamine (0.1 mole) and heated at 120C during 4 hours. The pressure is then gradually decreased to 19 Torr, and distillation gives 19.7 9 2-(2-thienyl)-ethylamine (Yield: 77%) which has a boiling point of 98C/l9 Torr.
Claims (6)
1. Process for the preparation of compounds having the formula:
(I) in which R1 and R2 each represent hydrogen or a lower alkyl or an optionally substituted phenyl radical, comprising aminating a derivative having the formula:
(II) in which radicals R1 and R2 have the above-mentioned meanings and R3 is an optionally substituted alkyl, aryl or aralkyl groups.
(I) in which R1 and R2 each represent hydrogen or a lower alkyl or an optionally substituted phenyl radical, comprising aminating a derivative having the formula:
(II) in which radicals R1 and R2 have the above-mentioned meanings and R3 is an optionally substituted alkyl, aryl or aralkyl groups.
2. Process as claimed in Claim 1, wherein the amination is carried out via the direct route, by reacting the derivative of the formula (II) with ammonia.
3. Process as claimed in Claim 2, wherein the reaction is carried out in the hot, in an autoclave.
4. Process as claimed in Claim 1, wherein the derivative of the formula (II) is reacted with phthalimide, to give a compound having the formula:
(III) which is subsequently transaminated with an amine or with hydrazine hydrate.
(III) which is subsequently transaminated with an amine or with hydrazine hydrate.
5. Process as claimed in Claim 4, wherein the reaction of the derivative of the formula (II) with phthalimide is effected in the presence of a base.
6. Process as claimed in Claim 4, wherein the amine is diethylenetriamine, benzylamine or ethanolamine.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7503142A FR2299332A1 (en) | 1975-01-31 | 1975-01-31 | PROCESS FOR PREPARING (THIENYL-2) -2-ETHYLAMINE AND ITS DERIVATIVES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1055509A true CA1055509A (en) | 1979-05-29 |
Family
ID=9150600
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA245,047A Expired CA1055509A (en) | 1975-01-31 | 1976-01-30 | Process for the preparation of 2-(2-thienyl)-ethylamine and derivatives thereof |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS51118760A (en) |
| BE (1) | BE837552A (en) |
| CA (1) | CA1055509A (en) |
| CH (1) | CH613700A5 (en) |
| DE (1) | DE2602846C2 (en) |
| ES (1) | ES444036A1 (en) |
| FR (1) | FR2299332A1 (en) |
| GB (1) | GB1469226A (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2415671A1 (en) * | 1978-01-25 | 1979-08-24 | Parcor | PROCESS FOR PREPARING 2-AMINO 2-ETHYL-2-THIOPHENE BY ELECTROCHEMICAL METHOD |
| NZ223583A (en) * | 1987-02-26 | 1990-02-26 | Merrell Dow Pharma | 2- or 3-thienyl-or-furyl-2-propyn-1-amines and antihypertensive compositions |
| EP0439404B1 (en) * | 1990-01-25 | 1995-10-25 | Sanofi | Preparation of 2-(2'-thienyl) alkylamines and derivatives thereof and synthesis of 4,5,6,7- thieno [3,2-c] pyridine derivatives therefrom |
| DE10248479A1 (en) * | 2002-10-17 | 2004-05-06 | Consortium für elektrochemische Industrie GmbH | Preparation of 3-halo-1-thienyl-1-propanone, useful as intermediate for duloxetin an inhibitor of neurotransmitter uptake, by Friedel-Crafts reaction of thiophene and halopropionyl chloride |
| DE10248480A1 (en) * | 2002-10-17 | 2004-05-06 | Consortium für elektrochemische Industrie GmbH | Preparation of 3-thienyl-3-hydroxy-1-aminopropane derivatives, useful as intermediates for duloxetin an inhibitor of neurotransmitter uptake, by reacting 1-halo compound with amine in closed system |
-
1975
- 1975-01-31 FR FR7503142A patent/FR2299332A1/en active Granted
- 1975-12-12 CH CH1613775A patent/CH613700A5/en not_active IP Right Cessation
-
1976
- 1976-01-02 ES ES444036A patent/ES444036A1/en not_active Expired
- 1976-01-09 JP JP239376A patent/JPS51118760A/en active Granted
- 1976-01-14 BE BE163500A patent/BE837552A/en not_active IP Right Cessation
- 1976-01-27 DE DE19762602846 patent/DE2602846C2/en not_active Expired
- 1976-01-30 CA CA245,047A patent/CA1055509A/en not_active Expired
- 1976-01-30 GB GB384976A patent/GB1469226A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| BE837552A (en) | 1976-07-14 |
| DE2602846C2 (en) | 1986-02-13 |
| DE2602846A1 (en) | 1976-08-05 |
| JPS6225666B2 (en) | 1987-06-04 |
| FR2299332B1 (en) | 1979-02-23 |
| CH613700A5 (en) | 1979-10-15 |
| GB1469226A (en) | 1977-04-06 |
| JPS51118760A (en) | 1976-10-18 |
| FR2299332A1 (en) | 1976-08-27 |
| ES444036A1 (en) | 1977-04-16 |
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