Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
81~
~ ne present invention is concerned with a nPw
process for p-eparing 2-(thieny'-2j-ethylamine~ and
2-(thi2nyl-3)-ethylam~neq, a considerab,e numb~r Qf
w~.ich are known and used as intermediates Lor obtain-
ing deri~atives us~d in the chemical indu-~try ~g
pharmaceuticals.
q~he co~pounds preparea by the proce~s according
'o the preqent invention ha~e the general formulao-
~1 - ~ C~2-CH-~
\ S 2 R2
in which Rl and R2, which may be the sa~e or different,
are hydrogen a~om~ or straight-chained or branched
alkyl radi~als or heterocyclic or non-heterocyclic
aromatic radical~, such as thienyl, furyl, py~idyl,
phenyl or naphthyl, which are optionally mono- or poly-
sub~tituted.
The 2minoethyl radical and the ~ub~.ituent Rl mzy
be in any de~ired po~ition of the thiophene nucleusO
The comDound3 of general formula (I) ha~e already
been prepared ~y various ~;ethod~:
reduction of 2- or 3-~-nitrovinylthiophene~ with t~e u.~e
of lithium aluminium hydride (see R~To Gil~dorr and
F.F. ~ord, J. Org. Chem., 15, 807/195~; E. Campaigne
and w.c. McCarthy, J.A.C.S., 76, 4466J195~) or electro-
S~
--3--
chemically (see E`rench Patent Specification No. 78 01 992
now French Patent No. 2,415,671);
reduction of 2 (thienyl-2)- and 2-(thienyl-3)-aceto-
nitriles with lithium aluminium hydride (see B.F. Crowe
and F.F. Nord, J. Org. Chem., 15, 81/1950; E. Campaigne
and W.C~ McCarthy, loc. cit.) or with sodium ama:Lgam
(see F.F. Blicke and J.H. Burckhalter, J.A.C.S., 64,
477/1942);
by the Curtius degradation of 3-(thienyl-2)- and 3-
(thienyl-3)-propionic acids (see G. Barger and
A.P.T. Eassou, J. Chem. Soc., 2100/1938; E. Campaigne
and ~.C. McCarthy, loc. cit.);
starting from halide or arylsulphonate derivatives of
2-(thienyl-2)- or 2-(thienyl-3)-ethanol by direct
amination (see F.F. Blicke and J.H. Burckhalter, loc. cit;
French Patent Specification Np. 75 03 142 now French
Patent No. 2,299,332) or via a phthalimide intermediate
(see French Patent Specification No. 75 03 142).
However, these various processes, which are difficult
to cary out, do not give good yields which are of
interest for use on a large scale.
It is an object of the present invention to provide
a process for obtaining compounds of general formula
(I) which is simple and not very laborious.
In order to achieve this object, in practice,
as starting material there is used a compound of the
general formula:-
1~:058 11
Rl ~ CH-C(R2~-N2 (IV)
in which Rl and R~ have the sam~ meanings a~ in general
formula (I), which may k~ pr pared by variou~ '~nown
methods, fo_ example by condensing a compound of the
general ~ormula:-
R2 CH2 ~2 ( I I )
in which R2 has the ~me meaning as in ~neral formula
~ T ~, with a carbonyl deriv~tive of the general ormula:-
.
~1 ~ C~O
in which Rl has t~e same meaning a~ in general formula
~I), operating under known conditions, to give a compound
of the general ~ormula:-
Rl ~ CH=C(R2)~02 (IV)
\ S
in which Rl and R2 have the ~ame meanings as in g~neralformula (I).
; Thus, according ~o th~ pre~ant invention, there
is provid~d a proces~ for preparing compounds of g~neral
formula ~I), wherein
a) a compo~nd of general formula ~IV) is ~ubjected ~o a
~L~O~
catalytic hydrogena~ion reacti~n under known conditions
to give a co~pound of the general formula-~
Rl ~ C~2--C=~--OH ( V
S R2
in whic~ Rl and R2 h~ve the 3ame ~eanings a~ above a~d
bj ~he ~ompound of ge~eral fonmula (V) i~, in kurnt
also converted by catalytic hydrogenation into a compound
of general fonmula ~I~ but under condition~ different
from tho~e used in the pr~viou~ step~
Generally ~p~aking, obtaîning com~ounds o~ the
arylethylamino t~pe according to the followi~ equation:
~2
: Ar-CH=C-~O~ ~ Ar-C~2~ 2
I catalyst
R R
i.e. by the catalytic hydrogenation of ~-nitrovi~yla~yl
compounds, i~ already Xnown~ However, it ha~ never been
used in ca5e~ in which the aromatic radical i~ thiophene.
~everthele~, there has prPviou~ly been de~cribed the
hydrogenation of 2-~-nitrovinyl~hiophene but limited
to obtaining th~ oxime of 2-(thienyl-2~-acetaldehyde
and carried o~t in the pre3ence o~ palladium (~ee
L. ~h. Freidlin, E.F. Litvin and V.M. Chursina, Khimiya
G. et Soed., 3, 22/1967, Chem. A~., 67, 73465 y) but
the quantitie~ of catalyst employed (0.200 g. of metallio
palladium per 0..775 g. of sub~trate to be hydrogenat2d)
- s -
exclude all reasonabl~ indu~trial application o~ the
proc2ss: the p~oportion of palladium u~ed is, in effect,
mor~ than 25~, referred to the su~strate~
In contradist.inction thereto, by the process
according to the presPnt invention, ~-(thienyl-23- and
2-(thienyl-3)-ethylamines are obtained under conditions
which ar~ si~ple to carry out and whic~ are not expensive
because of the ~mall amount3 of catalyst employedO
The ~roces~ according to th~ pres n~ invention is,
in particular, characterised by carrying out the
reduction in ~wo stag~s.
In ~he irst stage, a compo~nd of general formula
~IV) is hydrogenated in a non-alkaline medium in a
solvent medium, which may ~e an alcohol, suc~ as methanol,
ethanol or i~opropanol, or an organic acid, 3uch as
formic acid, acetic acid or proplonic acid, ox, still
more advantageously, in a m1xture of two solvent~ ea~h
selected ~rom one of the group~ of solvents mentioned
above, for example a mixture of ~ethanol or ethanol and
acetic acid. The hydrogenation is carried out in the
presence o~ a met~l catalyst, for example palladium,
platinum, ruthenium, rhodium or iridium~ -
l~e metal catalyst i~ ad~tantageously diluted with
10 to 100 time3 it-~ w2ight of a support material, for
example char~oal, alumina or barium su~phate, and,
generally spea}cin~, use is mads of a ~uantity which i5
from 1 to 10~o of the amount or su}:strate to ):~ hydrogenate~,
~ZOS811
, ~ ~
which corresponds to amounts of 1/10,000 to 1/100 of
palladium. The hydrogenation i~ carried out under a
hydrogen pressure which is gen~rally rom 1 to 100
atmosphere~ and preferably from. 5 to 25 atmo~phere~
at a temperature which i~ generally from ~0 t.o 100C.
and preferably from 30 to 60C. The dura~ion of the
oper~tion i~ g~n~rally from 30 minutes to several hours~
In the s2cond ~tage, the derivative of generaL
formula (V), isolated in appropriate manner from the
reaction mixture, is, after removal of the catalyst,
hydrogenated in a solvent medium, which may be a~
alcohol, for example met~anol, ethanol or i~opropanol,
which, in order to avoid the formation of secondary
amines, advantageously contain~ ammcnia in a dissol~ed
state. The hydrogenation is carried out in the presen~e
of a metal cataly~t and particularly of nick~l, which
may be Raney nicX~l or nickel deposited on a ~upport,
such as silica or alumina, the quantity of meta~ c2talys~
~s~d being f rom 1 to 10% of the ~ubstrate to be hydrogen~
ated. m e hydrogenation i~ carried out und~r a hydrogen
prPssure of gen~rally from 1 to 100 a~mospheres and
preferably of from 5 to 25 a~mo~ph~res a~ a temperaturQ
which i3 generally from 20 to 100C. and preferably fro~
40 to 80~C . The duration of the operation is generally
from 30 minutes to several hours~
The co~pound~ thus obtained of general formula (I)
may sub~equently be isolated and purified according to
~L2~
~_ .
conventional methods. In order to car~y out these
operations, it may ~e advantageous to con~7ert the free
bases of general formula (I) into their ~alts, or
example their acid aàdition salts, by rea~tion wnth
mineral or organic a ids. Starting from the salts,
the free basas of gene~al formula (I) may ~e liberated
by known method~.
~ te pr2sent invention is also concerned with ~he
internnediates obtained at different stages of the
synthesis, i.e. th~ compounds of general formula:-
.
~1 ~ CH2-C=~--~ (V)
S R2
in which Rl ~nd R2 have the same meanings as above;
and the compounds of the general fo~.tula:-
Rl ~ CH2-C~ 2 ~I)
\S R2
in which Rl and R2 have the same meanings as a~ove.
The following Examples are given for the purpo
of illustrating the present invention:-
Exam~le 1.
_
a) 2-~tienylacetaldehYde oxime~.
,
~ A ~olution of 100 g. (0.645 mole) 2 (thienyl-2)-
51~11
_9_ !
nitroethylene in 2 litres of a mixture of acetic acid
and ethanol ~75/25 v/v) i~ hydrogenated in an autoclave
at 35C. under a pressure of 20 bar~ in the pre~ence of
S ~. of palladium-charcoal (5~) until ab~orption of
hydrogen cea~e~ ( duration: about 2 hour~ ~ . Af ter
filtering off the catalyst and washing it with e-thanol,
the ~olution obtain~d is evaporated in a vacuum at S0C.
The oily residue obtained is taken up i~ 500 mlO met~ylene
chloride and the solution is succes~ively washed with an
approximately lN aqueou~ solution of ~odium ~axbonate
and then with water and finally evaporat~d to give 97 g.
of the oximes (mixture of 3yn and ant~3 o 2~thienyl-
acetaldehyde in the form of ~n orange-yellow oil which
is used as such ln the following step.
b~ m e mixture of oximes obtained above, in solukion
in 2 litres of methanol saturated with ammonia, is
hydrogenated in an autoclave at 60C. at a pre~sure of
20 bar~ in the pre3ence Qf 10 g . of Raney nicXel until
ab~orption ceases (duration about 20 hour~)u A~t2r
filtering off the cataly~t and washing it wi~h methanol,
the solution is evaporated. The oily re~idue obtained
i~ added to 500 ml. toluene. The organic pha~e is
extracted with approximately 1~ aqueou~ hydrochloric
acid. The aaueous acid pha~e i5 isolat2d and rendered
al~aline with an approx.imately 1~ aqueou~ solution of
~odium carbonate and then extracted with toluen80 The
addition to the isolated organic phase of a 301ution
i8
-lo
of ~aseou~ hydrogen chloride in dii~opropyl etner
bring~ a~out the formation of a precipitate which i ~ !
filtered of~ and dried~ The7e are thus obtained 68 g.
(yield 65% of theory, referred to ths ~-~thienyl-2)-
nitroethylene u~ed), of the hydrochloride o~ 2-~thienyl-
2)-ethylamine in the form of white crystals, ~.p. 2G2 CO
AnalY~
C6H9NS.HCl (M.W. 163.67)
calc. : C 44.03~, H 6.15%: N 8.55%
found : 43.98%- 6016%: s.s4æ
~e~=_ L-
Operating under Lhe reaction condition~ described
in Example 1 but using 5% r~odium/charcoal instead of
5% palladium/cnarcoal, there is obtained the ~esired
hydrochloride in a yield of 66% of theory, m.p. 216C.
Analy~
C6~gNS HCl ~M.W. 163.67)
calc. : C 44.03%: H 6.15%~ 8.55%
found : 43.92%, 5.la%, 8,5G%
~-
1- e~hyl-2-~thienyl-3 ~ t3~5~ a~Zah=~E~
operating under the reaction conditio~ used in
Example 1 ~ut u~ing S~ platinum/char~oal instead of 5%
palladium/charcoal, there is obtained the desired hydro-
chloride in a yield of 81% of theory, m. p . 13aC ~,
S81:3L `
Analy3i ~;:
C7Hll~S.,HCl~MoW~ 177 ~ 69 ~
calc . : C47 ~ 31%~ H ~ . 80%, ~1 7 0 88%
found: 47.5~%, 6.,35% 7.92%
