Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
-- 1059137
m is invention relates to a new p~ocess for the preparation of
2-oxo-1-pyrrilidinylacetamide or piracetam, namely a compound having the
formula
~, .
CH2-C0-NH2 , and to the intermediates used to
produce such compound.
Piracetam is a so-called cerebrotonicum, which is used for in- -
stance in travel sickness and the therapy of locomotorial diseases, hyper-
tension and epilepsy. It is widely used also in geriatry for improving
cerebral activity. m e use of piracetam is thus very wide and the toxicity
is 1c~7.
The preparation of piracetam has previously been described, e.g.
in U.S. Patent No. 3,459,738 issued Aug. 5, 1969 to Henri ~orren, Forest,
Belgium, assign~r to UCB (Union Chimique-Chemische Eedrijven), Saint-
Gilles-Br~ssels, Belgium, wherein it is prepared either from the correspond- t
ing ester and ammonia or by reacting a metal salt of 2-oxo-pyrrolidine ~7ith r
chloroacetamide.
In the above identified U.S. Patent, the procedure commences either
from the alk~li metal salt of 2-ox~pyrrolidine or from 2-oxo-1-pyrrolidinyl-
acetic acid ester, which is prepared from the above mentioned aIkali salt
and chloroacetic acid ester. In the preparation of the sodium salt of 2-
oxopyrrolidine, either metallic sodium or sodium amide are used, and in
the synthesis of the amide from the ester, gaseous ammDnia is used. m us,
the process of the above identified U.S. Patent involves the use of danger-
ous raw 7naterials.
It would therefore be desirable to provide a process for the
preparation of piracetam which does not inv~lve the use of dangerous raw
material~. According to a broad aspect of the present invention, the
~uç--et n is prepared by ring closure reaction. By one variant, glycina-
i7, ~'
,.~
. ' '
~059137
mide hydrochloride is first reacted with 4-chlorobutyric acid ethyl ester
formung N-carbamoyLmet hyl-4-aminoputyric acid ethyl ester, which is a new
compound, which is then cvclized to piracetam by heating.
Thus, by~ a broad aspect of this invention an inçrovement is pro-
vided in a process for the preparation of piracetam (2-oxo-1-pyrrolidinyl-
acetamide), a therapeutically valuahle compound of the formula
-0
N -
Cil2 -CO-NH2
the step which comprises heating an amino acid ester of the form~la
CH2-CO-NH
~I ~ `,
\ CH2-CH2-CH2{0CC2H5,
thereby to split off ethanol and to cyclize the amino acid ester.
By one variant, the heating is at a temperature of 1~0 - 180C.
By anoth.er aspect, a process is provided for the preparation of
2-oxo-1-pyrrolidinylacetamide, a therapeutically valuable oompound of the
formula
~0 ~,,
CH2 -CO-NU2
which oomprises: boiling glycinamide hydrochloride and 4-chlorobutyric acid
ethyl ester together in an organic solvent in the presence of an acid binding
agent and a catalytic amount of potasslum iodide, thereby to form an amino
acid ester of the formula
, S,
. .
~,
:, , , ': , . ~, . . - , ,. . ;
' ;' ., ~ '
:' . . . , :, :. -
., : :
~`` 1059137
/ C 2 2
`
CH2-CH2-CH2-CC2H5;
and then heating the can?ound to a temperature of 160 - 180C, thereby to
split off ethanol and to cyclize the am mo acid ester.
By one variant, the organic solvent is an alcohol and the acid
binding agent is sodium carbonate.
By a variation thereof, the process includes the step of simul-
taneously distilling off split-off ethanol as it is formed.
In another aspect of the invention the N-carbamoylmethyl-4-amino-
butyric acid ethyl ester is prepared by reacting glycinamide hydrochloride
with 4-chlorobutyric acid. r
By a variant thereof, the reaction is carried out by boiling
glycinamide hydrochloride and 4-chlorobutyric acid ethyl ester in an organic
solvent in the presence of an acid binding agent and a catalytic amount of
potassium iodide.
- By a variation thereof, the organic solvent is alcohol, and the
acid binding agent is sodium carbonate. r
m e N-carbamoylmethyl-4-amino butyric acid ethyl ester is a new
con~ound providing another aspect of this invention.
From textbooks in chemistry (e.g. Houben-hTeyl: Methoden der
organischen Chemie, Stickstoffverbindungen II/III, Georg Thieme Verlag,
Stuttgart 1958, p. 529), it is known that amino acids, their esters, amides
and nitriles can be cyclized to lactames. Hcwever, the reactions of N-
substituted amino acids have not been studied much. m e process of a broad
aspect of this invention is thus to be considered a new ~7ay to sol~e the
~ piracetam synthesis. m e reaction scheme of the process of an aspect of
; this invention is the folla~7ing:
.. ...
` ~ 1059137
H2N-CH2-CO-~H2.HCl~Cl- OE 2-CH2-CH2 ~00C2H5
,,
CH -CO-NH '
Na2C3
~ N~ heating >
CH2-CH2-CH2-CO~c2H5
(I) ~
r
I _L O +C2H5H
'Nr
C1~2-CO-NH2
me intermediate I is a new oompound, which has not earlier been
described in the literature. Glycinamide hydrochloride and 4-chiorobutyric
acid ethyl ester are industrial raw materials. The reaction between them
is simple: the agents are boiled in an organic solvent, preferably an
alcohol, e.g. ethanol, in the presence of an equivalent am~unt of sodium
carbonate and a catalytic amount of potassium iodide. The formed inter- ~
mediate I can be heated to a temperature of 160 - 180C, without isolation t
of the pure product, which leads to ring closure. m e process is conse-
20 quently simple in its entirety and the yield is good.
The prncess of broad aspects of the invention has, when oompared
to the above identified U.S. Patent, the advantage that no dangerous raw ~ -
materials being used. m e process according to aspects of this invention
can therefore be carried out with remarkably simpler equipment.
The invention is illustrated by the following exa~ple:
Example 1
22.1 g of glycinamide hydrochloride, 30.1 g of 4-chlorobutyric -
acid ethyl ester, 21.2 g of sodium carbonate and 0.5 g of potassium iodide
i are refluxed in 100 ml of ethanol. ~hen the reaction is oompleted after
~h ~ - 3 a -
, .
':. , '' ' , : '
' ' , ' : ''','., . '": .''~,,.~'," ' ' '',, ' ,
, . . . .
~ 1059137
16 hours, the suspension is filtered and the ethanol is distilled off.
m e residue, 34.2 g (9. per cent), is composed of crude N-carb~mDylmethyl-
4-aminobutyric acid ethyl ester. This is a solid agent having a melting
point of 100 - 115C, but it has never been obtained in a quite pure state r
as it always contains small am~unts of piracetam.
The residue can be used in the foll~^~ing step without isolation.
It is heated to 170C. and the formed ethanol is distilled off. m e heating
is oontinued so long as ethanol distils over, then is cooled and crystallized r
from isopropanol. Yield 21.7 g of piracetam (total yield 76.4%). The
melting point is 150 - 152C. t
~,
,.
: ~ - 3 b -
