Note: Descriptions are shown in the official language in which they were submitted.
~06133(~Z
The present invention relates generally to a novel
process for the preparation of an acetonitrile derivative and
also to the derivative obtained by this process.
The invention is particularly concerned with a novel
process for the preparation of di-n-propyl acetonitrile of formula :
; CH3-CH2-CH2
/ CH-CN
CH3-CH2-CH2
Di-n-propyl acetonitrile is a known product which is
of particular interest for the preparation of compounds having
pharmacological properties. For example, di-n-propyl acetonitrile
can be used for the preparation of di-n-propyl acetamide, which
has extremely valuable neuropsychotropic properties, as described
in B.S.M. (French Special Medicament Patent) N. 2442 M.
Di-n-propyl acetamide can be easily prepared with
excellent yields, of the order of 83 %, when starting from the
di-n-propyl acetonitrile, by hydrolysing this latter compound,
for example, by means of an aqueous solution of 75 to 80 %
sulphuric acid and at a temperature between 80 and 130C.
The conventional processes for the preparation of di-n-
propyl acetonitrile are generally complicated and necessitate
the use of reactants which are dangerous for the manufacturing
personnel. For example, the preparation of di-n-propyl acetoni-
trile, when starting from di-n-propyl ketone, requires the use
of sodium cyanide, which is an extremely toxic product.
Moreover, certain phases in the preparation consist in
a hydrogcnation, which is always difficult to carry out on the
industrial plane.
The need for finding an industrial process for obtaining
di-n-propyl acetonitrile is thus of paramount importance.
Hitherto, the synthesis of acetonitrile substituted
in the ~-position by two propyl groups, starting from an ester of
-1- ~
~LCJ168302
cyanacetic acid, has only been subject to experimentation in the
case where each of the two propyl groups is an isopropyl group.
In this connection, mention may be made of the processes
described by MARSHALL /J. Chem. Soc., 2754-2761 (1930~J, by BROWN
and collaborators /J. Am. Chem. Soc., 77, 1083-1089 (19551/ and by
NEWMAN and collaborators /J. Am. Chem. Soc., 82, 873-8i5 (1960~ .
These processes are characterised by a succession of
three or four quite distinct stages or steps, starting from an
ester of cyanacetic acid, namely :
- an alkylation phase, which is common to all three processes, for
the purpose of obtaining a diisopropyl cyanacetic ester,
- a phase for elimination of the monoalkylated ester,
- a phase for saponification of the diisopropyl cyanacetic ester in
the case of the processes proposed by MARSHALL and NEWMAN and
collaborators,
- and a decarboxylation phase, either of the diisopropyl cyanacetic
ester in the case of the process proposed by BROWN and colla-
borators, or of the diisopropyl cyanacetic acid in the case of
the processes proposed by MARSHALL and by NEWMAN and colla-
borators
Thus, MARSHALL prepares diisopropyl acetonitrile from a
cyanacetic ester, by treating with sodium an alcoholic solution
of this ester and by causing this mixture to react for several
hours with an excess of isopropyl iodile. The monoalkylated
product is eliminated by means of a 10 % sodium hydroxide solution
and the crude dialkyl ester obtained by this procedure is then
~reated with a 35 % potassium hydroxide solution for 16 hours.
After acidification, the diisopropyl cyanacetic acid obtained
is decarboxylated by distillation in the presence of twice its
weight of molten potassium hydroxide.
BROWN and collaborators,for their part, obtain diisopro-
pyl acetonitrile first of all by treating, with isopropyl iodide,
~6~33(~2
a solution of cyanacetic ester in n-propanol containing sodium
n-propylate, this being effected by refluxing for 2 hours, and
then by again adding sodium n-propylate in n-propanol and iso-
propyl iodide. The reaction medium is once again heated under
reflux for 3 hours, the monoalkylated product is eliminated by
a 10 % sodium hydroxide solution and the diisopropyl cyanacetic
ester is then distilled several times in the presence of twice
its weight of potassium hydroxide.
Finally, NEWMAN and collaborators prepare diisopropyl
lQ acetonitrile by first of all carrying out a reaction, under
reflux for 3 hours, of ethyl cyanacetate with isopropyl iodide
in the presence of sodium ethylate in ethanolic medium, further
adding sodium ethylate and then isopropyl iodide and once again
heating the reaction medium under reflux for 3 hours. After again
adding sodium ethylate and then isopropyl iodide and heating for 2
hours under reflux, the diisopropylated derivative obtained is
washed with a 15 % potassium hydroxiAe solution and then hydrolysed
by means of an alcohblic solution of 35 % potassium hydroxide under
reflux for 26 hours and the diisopropyl cyanacetic acid is heated
to 180-200C in the presence of copper powder.
In view of the great similarity as regards chemical
structure between diisopropyl acetonitrile and di-n-propyl
acetonitrile, attempts have been made to prepare this latter
compound by applying the aforementiQned processes used for the
preparation of the diisopropyl acetonitrile.
Tests carried out with the technique proposed by
MARSII~LL only produccd insignificant yiclds Or purc di-i-propyl
acetonitrile, of the order of 20 %, if each synthesis intermediary
is purified, or 35 %, if each intermediary is used in the crude
state, these yields being calculated on the basis of the initial
cyanacetic ester. Furthermore, the intermediate products prepared
in this process are contaminated with impurities, which prevent
~68;~02
their use in the crude state. Thus, the crude di-n-propyl
cyanacetie aeid obtained according to MARSHALL, or aecording
to NEWMA~ and collaborators, is found to be contaminated by 18
to 25 %, and 32 to 34 %, respectively, of a product which seems
to be a di-n-propyl formamidoacetic ester.
Furthermore, the procedure proposed by BROWN and
collaborators, as it necessitates a double alkylation phase,
has proved to be inadequate for the preparation of di-n-propyl
acetonitrile. In effect, this product has been obtained in pure
form with yields which vary from 28 to 44 %, calculated from the
initial methyl cyanacetate.
Finally, the process proposed by NEWMAN and collaborators,
which necessitates a treble alkylation phase and is particularly
time-consuming, only provided yields in the region of 40 % of
pure di-n-propyl acetonitrile, calculated on the basis of the
initial cyanacetic ester. It has also been observed that the
saponification of the di-n-propyl cyanacetic ester leads to a
mixture of 10 % of di-n-propyl cyanaeetic acid and 5 % of
di-n-propyl eyanacetie amide.
In eonclusion, all of the aforesaid methods, applied
to the preparation of di-n-propyl acetonitrile, are essentially
distinguished by their eomplexity and their eonsiderable duration,
by the impurities obtained at the different stages, necessitating
the elimination of sueh impurities,for the subsequent stages,
and by the poor yields of the final di-n-propyl acetonitrile.
Consequently,it was essential to find a process for the
preparation of di-n-propyl acetonitrile which has the following
qualities O
- simplicity as regards procedure,
- shorter overall duration,
- higher yields,
- a production cost which is as low as possible,
~C~683~Z
so that it can be validly used on the industrial scale.
In accordance with the present invention, it has now
been discovered that di-n-propyl acetonitrile can be obtained in
accordance with such a process which can be used industrially,
starting from a cyanacetic ester.
Thus in accordance with the process of the invention,
di-n-propyl acetonitrile is prepared by reacting, in one single
stage and in a n-propanol medium, an ester of cyanacetic acid
of the general formula :
/ CN
H2C II
COOR
in which R represents an alkyl radical having from 1 to 4 carbon
atoms, preferably a methyl or ethyl radical, with n-propyl bromide
or n-propyl iodide in the presence of sodium n-propylate, then by
saponifying the crude estar thus obtained with a 10 to 20 %
solution of potassium or sodium hydroxide and by acidifying the
salt thus formed with a strong acid, such as for example hydro-
chloric acid, to obtain the crude di-n-propyl cyanacetic acid,
which is decarboxylated by heating to a temperature between
140C and 190C, this yielding the di-n-propyl acetonitrile.
The starting-products of formula II are either known
products which have been mentioned in the foregoing publications,
or products which can be obtained by known methods.
As regards the alkylation phase, the reactants are
utilised by adding, at a temperature between 45C and 55C, the
sodium n-propylate in n-propanol medium to a reaction medium
which comprises the cyanacetic ester and the n-propyl halide.
The alkylation reaction is then carried out under reflux for
about 3 hours.
Saponification of the crude di-n-propyl cyanacetic
ester is preferably carried out at a temperature between 60 and
~06~3~2
70C over a period of 3 hours in the proportion of 1.25 to 2 mols
of hydroxide/mol of ester, and the subsequent acidification is
effected, for example, with a 35 % hydrochloric acid solution,
at a temperature slightly lower than 40C.
In accordance with an alternative procedure, the
saponification phase can be carried out in presence of a quaternary
ammonium such as, for example, trimethylcetylamonium bromide,
benzyl trimethyl ammonium chloride or lauryl trimethyl ammonium
bromide. The concentration of quaternary ammonium may vary from
0,005 mol to 0.1 mol/mol of di-n-propyl cyanacetic ester. Tempe-
rature as regards saponification and the time necessary for this
operation will vary as a function of the quantity of quaternary
ammonium used.
For a concentration of quaternary ammonium of 0.1
mol/mol of ester, saponification will taXe place for 3 hours at
30C, and for a concentration of o.on5 mol/mol of ester, the
operation will be completed in 1 hour at 60 to 65C.
As regards the decarboxylation phase, this latter will
be carried out on the crude di-n-propyl cyanacetic acid at a
temperature between 140 and 190C and preferably between 175
and 190C.
In accordance with a modification of this last operation,
the decarboxylation of the di-n-propyl cyanacetic acid can be
carried out in one continous phase. After the acid concerned is
brought to a temperature of 185-190C and the decarboxylation
reaction initiated, di-n-propyl cyanacetic acid is continuously
introduced, with simultaneous elimination of the liberated carbon
dioxide gas and of the di-n-propyl acetonitrile which forms.
The process of the invention provides indisputable
advantages as compared with the processes disclosed in the
previously mentioned prior art.
In the first place, the process of the invention offers
~)6830Z
the possibility of obtaining considerable yields of pure di-n-
propyl acetonitrile, the yields being at least 80 % as compared
with the initial cyanacetic ester, whereas with the processes
suggested by the prior art, it has not been possible to obtain
yields higher than 50 % with respect to the same starting ester.
In addition, the process of the invention is definitely
more simple than those of MARSHALL, BROWN and collaborators, or
NEWMAN and collaborators, referred to above. For example, the
process of the invention permits the alkylation phase to be
carried out in one single operation, comprising a single use of
the n-propyl halide and alkali metal n-propylate.
By contrast, the process proposed by BROWN and colla- -
borators necessitates two successive additions of alcoholate and
of halide, while in accordance with the process proposed by NEWMAN
and collaborators the addition of alcoholate and of halide is
carried out in three successive operations for each product.
The times necessary for the alkylation and saponification
phases are also considerable in the case of the known processes :
at least 8 hours for the alkylation phase according to the process
proposed by NEWMAN and collaborators, and 26 hours for the
saponification phase, according to these same authors.
The process of the invention, on the contrary, enables
the corresponding alkylation and saponification phases to be
effected much more quickly than by means of the known processes.
As regards the saponification phase, the time which is
necessary for this operation will be advantageously reduced in
the presence of a quaternary ammonium, for example, the trimethyl
cetylammonium bromide. This quaternary ammonium offers in addition
the advantage of reducing the danger of hydrolysis of the nitrile
function of the di-n-propyl cyanacetic ester.
Furthermore, the decarboxylation phase of the know
processes involves the necessity, apart from a raising of the
~6~33(~
temperature, of adding a supplementary product, either potassium
hydro~ide or copper powder.
According to the invention, the decarboxylation phase
occurs simply by heating the di-n-propyl cyanacetic acid.
An additional disadvantage presented by the processes
suggested by the prior art, and more especially by the alkylation
phases envisaged in these processes, is concerned with the recovery
of the solvent, of the reactants which have not reacted and of the
by-products formed during the reaction.
This recovery, which is fairly difficult when using
sodium ethylate/ethanol or sodium methylate/methanol is facilitated
by the use of the sodium n-propylate/n-propanol pair, which
provides greater possibility of separation by distillation of the
unreacted n-propyl halide, of the ether formed during the reaction
and of the alcohol which may be liberated by transesterification
of the cyanacetic ester by the n-propanol.
All these disadvantages, presented by the processes
suggested by the prior art, increase the quantity of material to
be used, the labour force and the energy consumption, causing a
concurrent increase in the cost of production.
Among the disadvantages presented by the known processes,
the presence of harmful impurities at the different stages is
certainly not the least negligible.
These impurities, which are present at each phase of
the process, singularly complicate the successful performance of
the said process. Consequently, it is necessary for them to be
elimitated at each stage, thus considerably increasing the
- intermediate handling operations, which are always costly at
the industrial level.
For example, the processes suggested by the prior art
envisage the eli~lination of the monoalkylated product after
the alkylation phase, this being effected by means of 10 %
1~6830Z
potassium hydroxide.
The alkylation phase as envisaged within the scope
of the process according to the invention renders unnecessary the
intermediate purification of the di-n-propyl cyanacetic ester,
which may be used in its crude form.
It has, in fact, been observed that the use of the
alkylation reactants according to the invention, depending essen-
tially on the introduction of sodium n-propylate/n-propanol into
a medium formed by the ester of formula II and the n-propyl
halide, provides the particular advantage of avoiding to a maximum
extent the formation of monopropyl cyanacetic ester, which is
much greater when the n-propyl halide is added to the cyanacetic
ester/sodium-n-propylate mixture. This monopropyl cyanacetic
ester, does, in fact, eventually lead to the formation of valero-
nitrile, which is a particular nuisance and must be eliminated.
The use of the alkylation reactants in accordance with
the invention permits the content of valeronitrile in the final
di-n-propyl acetonitrile to be very;substantially reduced, this
content passing from approximately 3.6 % to only 0.3 % according
to the invention.
Furthermore, the use of sodium n-propylate/n-propanol
in accordance with the invention has been found to be much more
advantageous than the use of sodium ethylate/ethanol or the use
of sodium methylate/methanol, as proposed in the processes accord-
ing to the prior art.
It has, in fact, been established that the content
of monopropyl cyanacctic ester in the crude di-n-propyl cyanacetic
- ester, which subsequently leads to valeronitrile, is increased,
and can even vary from 2 to 5 % if the reflux temperature of the
reaction medium is too low at the time of the alkylation phase,
which is the case with methanol or ethanol.
It has also been found that the use of the sodium
_ g _
;8302
ethylate/ethanol pair can give rise to the formation of a not
inconsiderable quantity, in the region of 1 %, of n-propyl cyana-
cetic ethylate at the time of the alkylation phase.
Moreover, as previously mentioned, the saponification
of the crude di-n-propyl cyanacetate in accordance with the
conditions proposed by NEWMAN and collaborators, or by MARSHALL,
that is to say, by means of 35 % potassium hydroxide for 16 to
26 hours, leads to the formation of a crude di-n-propyl cy~nacetic
acid containing from 18 to 35 % of an impurity, which seems to be
a di-n-propyl formamidoacetate and has to be eliminated. This
last product does not, in fact, give di-n-propyl acetonitrile by
decarboxylation, but di-n-propyl acetamide.
Yet again, the process according to the invention avoids
this disadvantage and, at the same time, an intermediate puri-
fication of the crude di-n-propyl cyanacetic acid.
During tests carried out within the scope of the present
invention, attempts have been made to combine certain phases
characteristic of the process of the invention with phases which
are used by the previously mentioned prior processes.
For example, the dialkylation phase of the process
according to the invention, combined with the decarboxylation
stage of the di-n-propyl cyanacetic acid by being melted with
twice its weight of 85 % potassium hydroxide, at a temperature
between 190 and 360C, in accordance with the procedure proposed
by MARSHALL, only supplied 11 % of di-n-propyl acetonitrile with
respect to the cyanacetic ester used. In this method of procedure,
most of the di-n-propyl cyanacetic acid was transformed into
- di-n-propyl acetamide and di-n-propyl acetic acid.
A variation of the decarboxylation process proposed by
MARSHALL has also been carried out with di-n-propyl cyanacetic
acid, obtained according to the process of the invention, and
twice its weight of 98 % sodium hydroxide. This mixture, distilled
-- 10 --
1~6~3302
for 2 1/4 hours at 370C, only supplied 38.3 % of di-n-propyl
acetonitrile with respect to the di-n-propyl cyanacetic acid used.
Furthermore, the methyl di-n-propyl cyanacetate obtained
in accordance with the process of the invention, was distilled
in the presence of potassium hydroxide, following the procedure
of BROWN and collaborators.
By using twice as much by weight of 97.7 % potassium
hydroxide as of ester and by heating to 380C for at least 2
1/4 hours, only 28.4 % of pure di-n-propyl acetonitrile, relatively
to the initial cyanacetate, were obtained.
A similar test, carried out with the same quantity of
98 % sodium hydroxide, under the same conditions as regards
temperature and duration, provided a yield of 44.4 % of di-n-propyl
acetonitrile relatively to the initial cyanacetate.
From all the results set out above, it is obvious that
the process according to the invention constitutes an undoubled
advantage over the processes suggested by the prior art.
Furthermore, the process of the invention has proved
to be superior to the known process as used for preparing di-n-
propyl acetonitrile, which process has been previously referred to.
- The invention is illustrated by the following non-
limiting Examples :
EXA~PLE 1
Preparation of di-n-pro~l acetonitrile
a) Di-n-propyl cyanacetic acid
First of all, a sodium n-propylate solution was prepared
from 7.42 g (0.322 mol) of sodium and 180 ml of anhydrous n-
propanol, by heating with gentle reflux until complete dissolution
of the sodium.
Into a 500 ml spherical flask, equipped with a dropping
funnel, a mechanical stirrer, a thermometer and a condenser, above
which was disposed a calcium chloride trap, were introduced
-- 11 --
~6~30Z
16.95 g (0.141 mol) of ethyl cyanacetate and 40.69 g (0.33 mol)
of n-propyl bromide. This mixture was heated to 45C and then
there was added thereto, slowly and while stirring, the previous-
ly prepared solution of sodium n-propylate, keeping the tempera-
ture of the reaction medium at 50-55C by gentle external cooling.
With the completion of the operation of introduction,
the mixt~re was brought to reflux temperature in 30 minutes and
kept at this temperature for 3 hours. The n-propanol was then
distilled and the distillation stopped when the temperature of
the residual mass had reached 115C.
The crude ester obtained in this way was then treated
with a solution of 7.5 g of flaked sodium hydroxide in 67.5 ml
of water. The mixture was introduced into a 250 ml spherical
flask, equipped with a condenser, and then the reaction medium
was slowly brought to 60-70C. This temperature was maintained
for 3 hours, whereafter the mixture was cooled to about 50C and
the ethanol which had formed and the residue of n-propanol were
eliminated under a pressure of 70 mm.Hg. The solution thus
obtained was cooled to 20C and acidified, while stirring, by
addition of 26.25 g of 36 % hydrochloric acid. During this
operation, the temperature of the reaction medium was kept below
40C by cooling. Stirring was continued for 30 minutes, whereafter
the mixture was left standing for 30 minutes. The oily layer of
di-n-propyl cyanacetic acid was decanted and the aqueous phase
extracted with 35 ml of toluene. The extract in toluene was
then added to the decanted di-n-propyl cyanacetic acid, whereafter
the solution in toluene was washed, in a separation funnel, with
a solution of 1.5 g of sodium chloride in 14 ml of water. The
toluenic phase was decanted and the toluene distilled under
atmospheric pressure.
Using this procedure, 25 g of crude di-n-propyl cyanacetic
acid were obtained.
- 12 -
1~968302
b) Di-n-propyl acetonitrile
Into a 100 ml spherical flask fitted with a thermometer
and a condenser were introduced 25 g of crude di-n-propyl cyana-
cetic acid obtained by the method previously described, and the
mixture was heated on an oil bath.
Decarboxylation commenced at a temperature in the region
of 140C. The mixture was then brought to reflux temperature,
that is to say, to about 160C and then to 190C in 2 hours. This
- temperature was maintained until the release of gas was completed,
10 this taking 2 hours. The di-n-propyl acetonitrile thus formed
was then slowly distilled and the fraction passing over between
165C and 175C was collected. A second distillation was then
carried out.
Using this procedure, 14.7 g of di-n-propyl acetonitrile
were collected. B.P. : 170C.
Yield: 83 %, relatively to the ethyl cyanacetate used.
EXAMPLE 2
Preparation of the di-n-prop~acetonitrile
a) Di-n-proE~yl cyanacetic acid
Initially, a solution of sodium n-propylate was prepared
from 50 g ~2 at,g + 10%) of sodium and 804 g (1000 ml) of anhydrous
n-propanol, by heating to 50-55C for 60 to 90 minutes.
99.1 g (1 mol) of methyl cyanacetate and 270.6 g (2.2
mols) of n-propyl bromide were introduced into a 2-litre spherical
flask. While stirring, the mass was brought to 45-50C and, at
this temperature, the solution of sodium n-propylate in propanol
was regularly introduced. This operation lasted from 60 to 70
minutes.
When the operation of introduction was completed, the
mixture was refluxed for 3 hours. The n-propanol was then
distilled until a temperature of 120-125C was reached in the
residual mass. The crude ester obtained was then trea-ted with
1al6~302
500 g of a 10 % aqueous solution of sodium hydroxide and with
0.36 g of cetyl trimethyl ammonium bromide.
The mixture was brought to reflux for 1 hour, was then
cooled to about 50C, and thereafter the residual alcohols were
eliminated under reduced pressure (50 to 100 mm.Hg).
The solution obtained was cooled and then acidified,
without exceeding 40C, by means of 175 g of 36 % hydrochloric
acid. The mixture was maintained in this state for 30 minutes
and then the di-n-propyl cyanacetic acid was decanted. The lower
aqueous layer was extracted with 250 g of toluene. The two
organic phases were combined, washed once with 100 g of purified
water and the solvent eliminated by distillation under reduced
pressure, to obtain 154.5 g of crude di-n-propyl cyanacetic acid.
b) Di-n-propyl acetonitrile
__ _~ __ ______________
The previously obtained crude di-n-propyl cyanacetic
acid was transferred into a 250 ml spherical flask and progres-
sively brought to reflux, while eliminating the last traces of
toluene by means of a Dean-Stark system, until a temperature of
the mass in the region of 175 to 180C was obtained. Decarboxyla-
tion started in the reyion of 140C and the reaction was practi-
cally complete after 1 hour of reflux. The mixture was kept
for a total of a hours under reflux. The mass temperature reached
205-210C in the first few minutes of the refluxing operation, and
dropped down again and became stable in the region of 185C. The
mixture was then distilled at atmospheric pressure.
In this manner, 102.5 g of di-n-propyl acetonitrile
were recovered. Yield of crude product : 82 %, relatively -to the
methyl cyanacetate.
Yield of pure product : 80 %
EXAMPLE 3
Preparation of di-n-propyl acetonitrile
Into a 50-litre enamelled container were introduced
- 14 -
~683i~)2
30 kg of di-n-propyl cyanacetic acid. While stirring, heating
under reflux to 185-190C was carried out and the temperature
was maintained as such for 15 minutes~ The di-n-propyl aceto-
nitrile thus formed was distilled, while 69.4 kg of di-n-propyl
cyanacetic acid were continously introduced.
The speed of introduction was regulated as a function
of the speed of distillation of the nitrile, while the temperature
of the mass was maintained at 185-190C. The operation of introduc-
tion lasted for about 4 1/2 hours, during which 40.9 kg of crude
di-n-propyl acetonitrile were recovered. Distillation was continu-
ed by gradually raising the temperature of the mass to 206C and
until the operation was completed. This operation lasted 6 hours,
during which there were recovered 16.350 kg and then a further
8.980 kg of crude di-n-propyl acetonitrile.
The apparatus was brought under reduced pressure (about
100 mm.Hg) and a new fraction of 1.640 kg of di-n-propyl aceto-
nitrile was collected.
Using this procedure, 67.87 kg of crude di-n-propyl
acetonitrile were obtained.
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