PROCEDE POUR LA PREPARATION DE LA 2-(2-THIENYL)-ETHYLAMINE ET DE SES DERIVES

PROCESS FOR THE PREPARATION OF 2-(2-THIENYL)-ETHYLAMINE AND DERIVATIVES THEREOF

Abrégé anglais

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:
Image (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:
Image (II)

in which R3 is an optionnally substituted alkyl, aryl or
aralkyl group, and R1 and R2 are as defined for formula
(I).

- 1 -

Revendications

The embodiments of the invention in which an exclu-
sive property or privilege is claimed are defined as follows:

1. Process for the preparation of compounds having
the formula:

Image (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:

Image (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:

Image (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.

Description

1055509

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.

,~

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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

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(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.
EXAMPLE 1
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-


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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.