FI65232C - FREQUENCY REFRIGERATION FOR DI-N-PROPYL-ACETONITRIL - Google Patents

Description

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(32) (33) (31) Requested request »—Begird priorltet 15 · 03. 77

France-France (FR) 7707587 (71) Sanofi, Uo, avenue George V, 75008 Paris, France-France (FR) (72) Michel Chignac, Sisteron, Claude Grain, Volonne,

Charles Pigerol, Saint-Ouen, France-Frankrike (FR) (7 ^) Oy Borenius & Co Ab (5 ^ +) Process for the preparation of di-n-propylacetonitrile -Förfarande för framställning av di-n-propyl-acetonitril

The invention generally relates to a new process for the preparation of an acetonitrile derivative.

In particular, the invention relates to a new process for the preparation of di-n-propylacetonitrile of the following formula

Di-n-prooyl-acetonitrile is a known compound of particular interest for the preparation of compounds with pharmacological properties. Thus, di-n-propylacetonitrile can be used to prepare di-n-propylacetamide, which has very valuable neuropsychotropic properties, i.e., properties affecting the mental functions of the nervous system, as described in B.S.M. (in a French specialty drug patent) No. 2442 M.

Ni-n-propylacetamide can be readily prepared in excellent yields of the order of 83% by using 2,65232 di-n-propylacetonitrile as the starting compound and hydrolyzing this compound, e.g. with 75-80% aqueous sulfuric acid, 80-130%. ° C.

Conventional methods for preparing di-n-propylacetonitrile are generally complex and require the use of reaction components that are hazardous to the manufacturing staff.

Thus, the preparation of di-n-propyl acetonitrile from the starting di-n-propyl ketone requires the use of sodium cyanide, which is a highly toxic compound.

In addition, some manufacturing steps are based on hydrogenation, which is always difficult to implement on an industrial scale.

It is therefore very important to invent an industrial process for the preparation of di-n-propylacetonitrile.

Until now, only experimentally synthesized acetonitrile has been synthesized in the «position by two propyl groups, starting from a cyanoacetic acid ester in the case where each propyl group is an isopropyl group.

In this connection, mention should be made of the methods described by MARSHALL (J. Ghem.Soc., 2754-2761 (1930)) BROWN et al. (J. Am. Ghem. Soc., 77, 1083-1089 (1955)) and NEWMAN et al. (J. Am. Chem. 3oc., 82, 873-875 (1960)).

These processes are characterized by three or four successive, completely separate steps, starting from the cyanoacetic acid ester, namely: - an alkylation step common to all processes for the preparation of diisopropyl cyanoacetic acid ester, - a step of removing the monoalkylated ester, - diisopropyl a saponification step in the case of the method proposed by Marshall and Newman et al., and a decarboxylation step in the case of either diisopropyl cyanoacetic acid ester in the method proposed by Brown et al. or diisopropyl cyanoacetic acid in that method, proposed by Marshall and also by Newman and co.

65232 3 Marshall thus prepares diisopropylacetonitrile from cyanoacetic acid ester by treating an alcoholic solution of this ester with sodium and reacting this mixture with the excess isopropyl iodide for several hours. The monoalkylated compound is removed with a 10% solution of sodium hydroxide, and the crude dialkyl ester thus obtained is then treated with a 35% solution of sodium hydroxide for 16 hours. The reaction mixture is then acidified and the resulting diisopropylcyanoacetic acid is decaroxylated by distillation in the presence of twice its weight of molten sodium hydroxide.

Brown and partners, in turn, prepare diisopropylacetonitrile by first treating the cyanoacetic acid ester with isopropyl iodide in n-propanol containing sodium n-propylate by reflux for 2 hours, followed by the addition of sodium n-propylate in n-propanol and isopropyl. The reaction medium is then refluxed again for 3 hours, after which the monoalkylated compound is removed with 10% sodium hydroxide solution and the diisopropyl cyanoacetic acid ester is distilled several times in the presence of twice the weight of this ester of potassium hydroxide.

Finally, Newman and partners prepare diisopropylacetonitrile by first carrying out the reaction between ethyl cyanoacetate and isopropyl iodide by refluxing for 3 hours in the presence of sodium ethylate in ethanol medium, then adding more sodium ethylate and then refluxing the isopropyl iodide for 3 hours.

After re-addition of sodium ethylate and then isopropyl iodide and refluxing for 2 hours, the resulting diisopropylated derivative is washed with a 15% solution of potassium hydroxide, followed by hydrolysis with a 35% alcohol solution of potassium hydroxide, followed by refluxing for 26 hours. diisopropyl cyanoacetic acid is heated to 180 ...

To 200 ° C in the presence of copper powder.

Given the great similarity of the chemical structure of diisopropylacetonitrile and di-n-propylacetonitrile, attempts have been made to prepare the latter compound by applying the above-mentioned methods used to prepare diisopropylacetonitrile.

4,65232

Experiments performed using the method proposed by Marshall yielded pure di-n-propylacetonitrile with only negligible yields of the order of 20¾ in the case of purification of each synthetically prepared medium, or in the order of 35% in the case of each medium used crude. , these yields being calculated on the basis of the original cyanoacetic acid ester.

In addition, the intermediate resins prepared by this method are contaminated with impurities that prevent their use as raw. Thus, it has been found that the crude di-n-propyl-cyanoacetic acid prepared according to Marshall or Newman et al. Is contaminated with 18-25%, respectively 32-34% of a compound which appears to be a di-n-propyl-formamidoacetic acid ester.

In addition, the process proposed by Brovm and co-workers has proved unsuitable for the preparation of di-n-propylacetonitrile because this process necessarily involves a double alkylation step. This compound is obtained in pure yields of 28-44% based on the original methyl cyanoacetate.

In addition, according to the method proposed by Newman & co-workers, which requires the use of a triple alkylation step and which consumes a particularly long time, only about 40% of pure di-n-propylacetonitrile, based on the original cyanoacetic acid ester, was obtained. It has also been found that saponification of the di-n-propyl-cyanoacetic acid ester results in a mixture of 10% di-n-propyl-cyano-acetic acid and 3% di-n-propyl-cyano-acetic acid amide.

In conclusion, all the above methods applied to the preparation of di-n-propylacetonitrile are mainly known for their complexity and considerable time consumption, and further for the impurities formed in the different steps, which forces the removal of these main impurities before use in the subsequent steps, and still finally, di-n-propylacetonitrile is obtained only in poor yields.

It has therefore been essential to devise a process for the preparation of di-n-propylacetonitrile which is characterized by: - simplicity of processing 5 65232 - reduced time required - higher yields, - the lowest possible production costs so that the process can be successfully used on an industrial scale.

According to the invention, it has now been found that di-n-propylacetonitrile can be prepared by applying a process which can be used on an industrial scale, starting with cyanoacetic acid ester.

According to the invention there is provided a process for the preparation of di-n-propylacetonitrile which is characterized in that, in a single step, sodium n-propylate in an n-propanol medium is added to a reaction medium of 45 to 55 ° C formed by the following general formula

CN

H2c v. (H)

^ COOR

in which R represents an alkyl radical having 1 to 4 carbon atoms and n-propyl bromide or iodide, wherein the alkylation reaction is carried out under reflux, and the crude ester thus obtained is saponified at 30 to 70 ° C. at a temperature of 10 to 20% with a solution of potassium or sodium hydroxide, optionally in the presence of a quaternary ammonium salt, and the salt thus formed is acidified with a strong acid to give crude di-n-propyl cyanoacetic acid which is decarboxylated by heating at 140 to 190 ° C to di-n-propyl acetonitrile.

The starting compounds of formula (II) are either previously known compounds mentioned in the above publications or compounds which can be prepared by known methods.

The alkylation reaction is preferably carried out by refluxing for about 3 hours. The crude di-n-propyl-cyanoacetic acid ester is suitably saponified at 60-70 ° C for 3 hours using 1.25..2 moles of hydroxide / mole of ester, and then the reaction mixture is acidified with e.g. 36% hydrochloric acid solution slightly below 40 ° C :in.

6,65232 e.g. with 36% hydrochloric acid solution at slightly below 40 ° C.

According to an alternative method, the saponification step can be carried out in the presence of a quaternary ammonium compound, such as trimethylcetylammonium bromide, benzyltrimethylammonium chloride and lauryltrimethylammonium bromide. The concentration of the quaternary ammonium compound may range from 0.005 to 0.5 moles / mole of di-n-propyl cyanoacetic acid ester. The saponification temperature as well as the time taken for this saponification varies as a function of the amount of quaternary ammonium compound used.

At a concentration of 0.1 mol / mol of ester of the quaternary ammonium compound, saponification takes 3 hours at 30 ° C, while at a concentration of 0.005 mol / mol of ester, the reaction is completed within one hour at 60-65 ° C.

The decarboxylation step is in turn carried out using crude di-n-propyl cyanoacetic acid at 140-190 ° C, suitably 175-190 ° C.

According to a variant of this latter treatment, di-n-propyl cyanoacetic acid can be decarboxylated in a single continuous step. After that. the acid is heated to 185-190 ° C and the decarboxylation reaction is started, di-n-propyl cyanoacetic acid is continuously added, simultaneously removing the liberated carbon dioxide gas and the di-n-propyl acetonitrile formed.

The method according to the invention has undeniable advantages over the methods described in connection with the above-mentioned prior art.

In the first place, the process according to the invention makes it possible to prepare pure di-n-propylacetonitrile in considerably higher yields of at least 80%, based on the original cyanoacetic acid ester, whereas prior art capped processes have made it impossible to obtain yields greater than 50% from the same starting material. calculated on the ester.

In addition, the method according to the invention is clearly simpler than the above-mentioned methods described by Marshall, Brown and Kumpp., Or 7 65232

Newman and partner. have submitted. Thus, in the process according to the invention, the alkylation step can be carried out in a single treatment in which n-propyl halide and alkali metal n-propylate are used only once.

In contrast, the method proposed by Brown et al. Forces the addition of alcoholate and halide twice in succession, whereas the method proposed by Newman et al. have suggested an alcoholate and a halide are added in three successive treatments during the preparation of each compound.

The times taken for the alkylation and saponification steps are also considerably long when using the known methods, i.e. at least 8 hours when applying the alkylation step according to the method used by Newman et al. have proposed, and 26 hours for the saponification step of the method by the same authors.

In the process according to the invention, the corresponding alkylation and saponification steps can instead be carried out much faster than in the previously known processes.

The time required for the saponification step is considerably reduced in the presence of a quaternary ammonium compound, e.g. trimethyl-cetyl-ammonium chromide. In addition, the quaternary ammonium compound has the advantage that the risk of hydrolysis of the nitrile function of the di-n-propyl cyanoacetic acid ester is reduced.

In addition, in the decaroxylation step of the prior art methods, in addition to raising the temperature, an additional compound, either potassium hydroxide or copper powder, must also be added.

According to the invention, the decarhoxylation step takes place simply by heating di-n-propyl cyanoacetic acid.

Another disadvantage associated with the prior art processes, and in particular the alkylation steps of these processes, concerns the recovery of solvent, unreacted reaction components and by-products formed during the reaction.

This recovery, which is a relatively difficult operation in the case of using sodium ethylate / ethanol or 8,652,322 sodium methylate / methanol as pairs, can be facilitated by using sodium n-propylate / n-propanol as a pair, which makes it possible to separate the reaction by distilling unreacted n-propyl halide. ether and alcohol formed during the trans-esterification of the cyanoacetic acid ester and n-propanol.

All of these disadvantages inherent in prior art methods increase the amount of material used as well as the labor and power consumption required, which in turn increase manufacturing costs.

Of the disadvantages of the known methods, the presence of harmful impurities at various stages is by no means a negligible factor.

These impurities, which are present at all stages of the process, greatly complicate the successful implementation of the process.

Thus, it is necessary to remove these impurities at each stage, which considerably increases the processing of intermediates, which are always expensive on an industrial scale.

Thus, in prior art processes, the monoalkylated compound must be removed after the alkylation step, which is done with a 10% solution of potassium hydroxide.

In the alkylation step according to the invention, it is not necessary to purify the di-n-propyl cyanoacetic acid ester from time to time, but this can still be used crude.

!

In fact, it has been found that the use of the alkylation reaction according to the invention is overcome mainly due to the addition of sodium n-propylate / n-propanol to the medium formed by the ester of formula (II) and the n-propyl halide, the particular advantage of avoiding monopropyl -cyanoacetic acid ester formation, which occurs to a much greater extent in the case where n-propyl halide is added to a mixture of cyanoacetic acid ester and sodium n-propylate. This monopropyl cyanoacetic acid ester gradually leads to the formation of valeronitrile, which is a particularly harmful impurity and must be removed.

The use of alkylation reaction components according to the invention results in a significant reduction in the concentration of valeronitrile in the final di-n-propylacetonitrile, so that this reduction occurs from approximately 3.6% to 0.3% only due to the invention.

It has further been found that the use of sodium n-propylate and n-propanol according to the invention is much more advantageous than the use of sodium ethylate and ethanol or sodium methylate and methanol proposed in previously known methods.

In fact, it has been found that the amount of monopropyl cyanoacetic acid ester in the crude di-n-propyl cyanoacetic acid ester, which then leads to the formation of valeronitrile, increases and can vary up to 2 to 5% »if the reflux temperature of the reaction medium is too low during the alkylation step, as is the case with methanol or ethanol.

It has also been found that the use of sodium ethylate and ethanol causes a fairly considerable formation of n-propyl cyanoacetic acid ethylate, on the order of 1% during the alkylation step.

In addition, saponification of crude di-n-propyl cyanoacetate under conditions proposed by Newman et al. or Marshall, i.e. using a 35% solution of potassium hydroxide for 16 to 26 hours, results in the formation of crude di-n-propyl cyanoacetic acid containing 18 to 34% of the impurity which appears to be di-n -propyl formamidoacetate, which must be removed. This latter compound does not lead to the formation of di-n-propylacetonitrile but to di-n-propylacetamide upon decarboxylation.

Again, this disadvantage is avoided in the process according to the invention, while at the same time purification is carried out without purification between crude di-n-propyl-cyanoacetic acid.

In connection with the experiments according to the invention, an attempt has been made to compare some of the properties of the steps included in the method according to the invention with the steps of previously known methods.

Thus, the dialkylation step of the process of the invention combined with the decarboxylation step of di-n-propylcyanoacetic acid by melting this acid and twice its weight of 85% potassium hydroxide at 190-360 ° C according to the Marshall method gave only 11% di -n-propyl acetonitrile based on the cyanoacetic acid ester used. Applying the method in this way, most of the di-n-propyl cyanoacetic acid was converted to di-n-propyl acetamide and di-n-propyl acetic acid.

The decarboxylation process proposed by Marshall has also been modified to use the di-n-propyl cyanoacetic acid obtained by the process of the invention and twice the amount of 98% sodium hydroxide. Distillation of this mixture for 2 1/4 hours at 370 ° C gave only 38.3% di-n-propylacetonitrile based on the di-n-propyl cyanoacetic acid used.

Further, the methyl di-n-propyl cyanoacetate obtained by the process of the invention was distilled in the presence of potassium hydroxide using the method described by Brown et al. have suggested.

Using twice as much 97.7% potassium hydroxide as the ester (by weight) and heating at 38 ° C for at least 2 1/4 hours, only 28.4% of pure di-n-propylacetonitrile, based on the original cyanoacetate, was obtained.

A similar experiment performed using an equal amount of 98% sodium hydroxide at the same temperature and for the same time gave 44.4% di-n-propylacetonitrile, based on the original cyanoacetate.

From all the above results, it is obvious that the method according to the invention undoubtedly represents a great advance compared to the methods according to the prior art.

In addition, the process according to the invention has proved to be superior to the above-mentioned known processes, and applied to the preparation of di-n-propylacetonitrile.

The following examples illustrate the invention.

Example 1

Preparation of di-n-propyl acetonitrile 11 65232 a) Di-n-propyl cyanoacetic acid

First, a sodium n-propylate solution was prepared using 7.42 g (0.322 mol) of sodium and 180 ml of anhydrous n-propanol and gently boiled under reflux until the sodium was completely dissolved.

16.95 g (0.141 mol) of ethyl cyanoacetate and 40.69 g (0.33 mol) were added to a 500 ml spherical flask containing a dropping funnel, a mechanical stirrer, a thermometer and a condenser fitted with a trap containing calcium chloride. ) n-propyl-s-bromide. The mixture was warmed to 45 ° C, after which the above-prepared sodium n-propylate solution was slowly added with stirring, keeping the temperature of the reaction medium at 50-55 ° C with gentle external cooling.

After the addition was complete, the mixture was heated to reflux for 30 minutes and maintained at that temperature for 3 hours. The n-propanol was then removed by distillation, and the distillation was stopped, the temperature of the residual mass of the law had risen to 115 ° C.

The crude ester thus obtained was then treated with a solution of 7.5 g of sodium hydroxide flakes in 67.5 ml of water. The mixture was poured into a 250 ml spherical beaker with a condenser, after which the reaction medium was slowly heated to 60-70 ° C.

This temperature was maintained for 3 hours, after which the mixture was cooled and the ethanol formed and the remaining n-propanol were removed at 70 mm Hg. The solution thus obtained was cooled to 20 ° C and acidified by adding 26.25 g of 36% hydrochloric acid with stirring. During this treatment, the temperature of the reaction medium was kept below 40 ° C by cooling. Stirring was continued for 30 minutes, after which the mixture was allowed to slide for 30 minutes. The oily layer of di-n-propyl-cyano-acetic acid was decanted, and the aqueous phase was extracted with 35 ml of toluene. The toluene extract was then added to the decanted di-n-propyl cyanoacetic acid, after which the toluene solution was washed in a separatory funnel with a solution of 1.5 g of sodium chloride in 14 ml of water. The toluene phase was decanted and the toluene was distilled off at atmospheric pressure.

In this way, 25 g of crude di-n-propyl cyanoacetic acid were obtained.

12 65232 b) Di-n-propylacetonitrile was added to a 100 ml spherical beaker equipped with a thermometer and a condenser, 25 g of di-n-propyl cyanoacetic acid prepared as described above, and the mixture was heated in an oil bath.

Decarboxylation began at about HO ° C. The mixture was then heated to reflux, i.e., about 160 ° C, and then within 2 hours to 190 ° C. This temperature was maintained until gas evolution ceased, which took 2 hours. The di-n-propylacetonitrile thus formed was then slowly distilled, and a fraction distilled at 165-175 ° C was collected. This was further distilled to give 14.7 g of di-n-propylacetonitrile, b.p. 170 ° C, yield 83% of the ethyl cyanoacetate used.

Example 2

Preparation of di-n-propyl acetonitrile a) Di-n-propyl cyanoacetic acid

First, a sodium n-propylate solution was prepared using 50 g (2 at.g + 10%) of sodium and 804 g (1000 ml) of anhydrous n-propanol and heating at 50-55 ° C for 60-90 minutes.

Then, 99.1 g (1 mole) of methyl cyanoacetate and 270.6 g (2.2 moles) of n-propyl bromide were added to a 2-liter spherical cooking flask. The mass was heated with stirring to 45-50 ° C and at this temperature a propanol solution of sodium n-propylate was gradually added over 60-65 minutes.

At the end of the addition, the mixture was boiled for 3 hours under reflux. The n-propanol was then removed by distillation until a residual mass temperature of 120-125 ° C was reached. The resulting crude ester was then treated with 500 g of a 10% aqueous solution of sodium hydroxide and 0.36 g of cetyltrimethylammonium bromide.

The mixture was refluxed for 1 hour, then cooled to about 50 ° C and the residual alcohols were removed under reduced pressure (50-100 mm Hg).

The resulting solution was cooled and then acidified using 175 g of 36% hydrochloric acid, not allowing the temperature to rise above 13,652,32 ° C. The mixture was kept in this state for 30 minutes, after which the di-n-propyl cyanoacetic acid was decanted. The aqueous layer below was extracted with 250 g of toluene. The two organic phases were combined, washed once with 100 g of purified water, after which the solvent was removed by distillation under reduced pressure to give 154.5 g of crude di-n-propyl cyanoacetic acid.

b) Di-n-propyl acetonitrile

The crude di-n-propyl cyanoacetic acid obtained above was placed in a 250 ml spherical beaker and gradually heated to reflux while removing the last residues of toluene using a Dean-Starck system until a residual mass temperature of about 175-180 ° C was reached. Decarboxylation began at about 140 ° C and the reaction was virtually complete after one hour of reflux. The mixture was refluxed for a total of 2 hours.

During the first few minutes of this redistillation, the temperature of the pulp rose to 205-210 ° C, then dropped again and stabilized at about 185 ° C. The mixture was then distilled at atmospheric pressure.

In this way, 102.5 g of di-n-propylacetonitrile were obtained, with a crude product yield of 82%, based on methyl cyanoacetate. Yield of pure product 80%.

Example 3

Preparation of di-n-propyl acetonitrile

30 kg of di-n-propyl cyanoacetic acid was added to a 50 liter enameled tank. Boiled under reflux and stirred at 185-190 ° C, the temperature was maintained at this value for 15 minutes. The di-n-propyl acetonitrile thus formed was distilled off, and 69.4 kg of di-n-propyl cyanoacetic acid was continuously added.

The addition rate was adjusted as a function of the nitrile distillation rate, and the temperature of the reaction mixture was maintained at 185-190 ° C. The addition took about 41 hours, during which time 40.9 kg of crude di-n-propylacetonitrile was recovered. Distillation was continued gradually by raising the temperature of the mixture to 206 ° C until the reaction was complete. It took that

Claims (4)

14,652,32 6 hours during which 16.35 kg and then a further 8.98 kg of crude di-n-propylacetonitrile were recovered. 5 The apparatus was subjected to vacuum (approximately 100 mm Hg) and 1.64 kg of di-n-propylacetonitrile was recovered as a new fraction. In this way, 67.87 kg of crude di-n-propylacetonitrile were obtained. A method of the formula CH3-CH2-CH2. CH-CN (I) CH3-CH2-f: H2 ^ /, for the preparation of di-n-propylacetonitrile, characterized in that in a single step sodium n-propylate in n-propanol medium is added 45 .. To a .55 ° C reaction medium formed from cyanoacetate of the following general formula ^ CN H 2 CQ (II) ^ COOR, wherein R represents an alkyl radical having 1 to 4 carbon atoms and n-propyl bromide or iodide, the alkylation reaction being carried out under reflux, and the crude ester thus obtained is saponified at 30 to 70 ° C with a 10 to 20% solution of potassium or sodium hydroxide, optionally in the presence of a quaternary ammonium salt, and the salt thus formed is acidified with a strong acid to give crude di-n-propyl cyanoacetic acid, which is decarboxylated by heating to 140-190 ° C to di-n-propyl acetonitrile. Process according to Claim 1, characterized in that the saponification is carried out in a ratio of 1.25 to 2 moles of potassium or sodium hydroxide per mole of crude ester. Process according to Claim 1, characterized in that the saponification is carried out in the presence of 0.005 to 0.1 mol of quaternary ammonium compound / mol of crude ester. Process according to Claim 1, characterized in that the reaction mixture is acidified with 36% hydrochloric acid at a temperature of at most 40 ° C. Process according to Claim 1, characterized in that the decarboxylation is carried out continuously by adding di-n-propyl cyanoacetic acid and at the same time removing the di-n-propyl acetonitrile formed. A compound for the preparation of di-n-propyl acetonitrile with the formula CH3-CH2-CH2-^ (TCH-CN (I) CH3-CH2-CH2 '' '^ kännetecknat därav, att man i ett own steg tillsätter sodium sodium-n -proclate in n-propanol medium to a reaction medium at a temperature of 45 to 55 ° C, and then to the cyanoacetate in the form of CN code «2C« V. <H> COOR