Method of preparation of a derivative of acétonitrile and derived obtained by this process.

The present invention relates, in general, to a novel process for preparing a derivative of acetonitrile and at derivative obtained by this method.

The invention relates, in particular, a novel method for preparing di-n-propylacétonitrile of formula:

HM

^ ^ ^ I-T-CH-CN

Cîlj aparatus Ch,, """"

3, 2 2

Di-n-propylacétonitrile is a known product of particular interest for the preparation of compounds having pharmacological properties. For example, di-n-propylacetonitrile may be used for preparing di-n-propylacetamide, which has properties neuropsychotropic extremely interesting, as described in the B.S.M. b.⁰ 2442 METERS.

Di-n-propylacetamide can be prepared easily and with excellent yields, on the order of 83 initially di-n-propylacétonitrile by hydrolyzing the compound, for example by means of an aqueous solution .'d ' acid 75 to 80 sulfuric % and at a temperature between 80° and 130 °c.

Conventional methods for preparing di-n-propylacétonitrile are generally complicated and require hazardous reagents for manufacturing personnel. For example, the preparation of the di-n-octyl propylacétonitrile initially di-n-Ketone uses sodium cyanide, highly toxic product.

In addition, some preparation phases involve hydrogenation always difficult to perform on the industrially.

Searching for an industrial process for obtaining di-n-propylacétonitrile therefore remains primary trait.

Hitherto, the synthesis of acetonitrile substituted in the alpha position by two groups at the beginning of the propyl ester of methoxyacetic acid has not been experienced that in the case where each of the two groups is a propyl isopropyl group.

To this end -, include of methods described by MRSHALL00~OJ Mal. Soc., 2754 - 2761 (1930.17, by Brown et al.. The AM.

Mal. Soc., 77, 1083 - 1089 (195517 and by NEMAN et al. / " J-. The AM.

Mal. Soc., 82, 873 - 875 (1960 ΐ · 7

These methods are characterized by a succession of three or four very distinct steps at start up of methoxyacetic acid ester, namely:

- a phase alkylation common to the three methods for obtaining an ester diisopropylcyanacetic,

- an elimination of the ester monoalkylated,

- a phase of saponification of the ester diisopropylcyanacetic for procedures and Marshall's HEWMAH and glued, and

- a phase of decarboxylation diisopropylcyanacetic ethyl ester in the case of the method of browït et, or acid diisopropylcyanacetic for procedures Marshall's and ïïewmah and colloidal

3 Thus, Marshall's prepares the diisopropylacétonitrile initially methoxyacetic ester by treating with sodium an alcoholic solution of this ester and reacting the mixture for several hours with an excess of isopropyl iodide. The monoalkylated product is removed by means of a sodium hydroxide solution to 10 % and the raw dialkyl ester thus obtained is then treated with a solution of potassium hydroxide to 55 $during sixteen heureso after acidification, acid is decarboxylated diisopropylcyanacetic obtained by distillation in the presence of two times its weight of molten potassium hydroxide.

BROWF and glue, in turn, obtains the diisopropylacétonitrile firstly by processing, by isopropyl iodide, a methoxyacetic ester solution in n-propanol containing n-propoxide sodium and, at reflux during two hours, followed by repeating the addition of n-propoxide sodium in n-propanol as well as addition of isopropyl iodide. The reaction medium is again refluxed during three hours, and the monoalkylated product is removed by a solution of sodium hydroxide to 10 with fo and the ester diisopropylcyanacetic is then distilled several times in the presence of two times its weight of potassium hydroxide.

Finally, HEWMAH - et al, prepare the diisopropylacétonitrile by reacting a first time, at reflux, for three hours, the cyanacé tatetate.d'ethyl with isopropyl iodide in the presence of sodium ethylate ethanolic, renewing and then adding sodium ethylate, then of isopropyl iodide and with refluxing the reaction medium again for three hours. After a further addition of sodium ethylate of isopropyl iodide and then further heating for two hours at reflux, the derivative diisopropylé obtained is then washed with a solution of potassium hydroxide to 15 i° and by hydrolysis using an alcoholic solution of potassium hydroxide to 35 i° at reflux for twenty-six hours and diisopropylcyanacetic acid is heated to 180 and 200 °C in the presence of copper powder "

Because of the great similarity of chemical structure between the diisopropylacétonitrile and di-n-propylacétonitrile, an attempt has been made to apply to the preparation of the latter compound, the methods mentioned above for the preparation of O-diisopropylacétonitrile

Experiments using the technique of EARSHA1L have repayments of yield derisory di-n-propylacétonitrile pure, of the order of 20% if each synthetic intermediate is purified or 35' % if each intermediate is used in the raw state, these yields being calculated methoxyacetic ester from starting "in addition, the intermediates prepared in this method are obtained soiled of harmful impurities of prohibiting the use of such intermediates raw" thus, the di-n-propylcyanacetic obtained crude Marshall or 91/8^- et al ", proves tarnished by respectively 18 to 25 $and 32 to 34 1 a product that appears to be an ester of di-n-propylformamidoacetic.

On the other hand, the technique of Brownian^- et al "requiring a phase alkylation in two time, revealed the poverty of this method for preparing di-n-propylacétonitrile. indeed, this product, in pure form, was obtained in yields ranging from 28 to 44 $from the starting methyl cyanacétate"

Finally, according to the method of Newman and al, requiring a phase alkylation in three time as well as a particularly important for carrying out this method, but it is obtained that yields of approximately 40 % di-n-propylacétonitrile pure calculated methoxyacetic ester from starting. It has been found further that the saponification of the ester of di-n-propylcyanacetic leads to a mixture of acid (10 %) and D.' amid (57°) di-n-octyl propylcyanacetic.

In conclusion, all of the above methods, applied to the preparation of the di-n-octyl propylacétonitrile, differ from one another basically their complexity and their long time ^ impurities obtained by the various steps requiring their removal for the later stages of yield and lean di-n-propylacétonitrile end.

Therefore, it is essential to find a process for preparing di-n-propylacétonitrile having the following properties:

- simplicity of use,

- overall duration less important,

- higher yields,

- cost as low as possible,

such that it can be used validly industrial scale "

It has now been found, according to the present invention, it is possible to obtain di-n-propylacétonitrile according to such a method industrially usable initially methoxyacetic ester.

Thus, according to the method of the invention, prepared di-n-propylacétonitrile by reacting, in a single step and in medium npropanol, methoxyacetic acid ester of general formula:

wherein R represents an alkyl radical having from 1 to 4 carbon atoms, preferably methyl or ethyl, with bromide or iodide n-propyl/presence of n-propoxide sodium, and then saponifying the crude ester thus obtained with a solution of potassium hydroxide or sodium 10 to 20 $and by acidifying the salt so formed by a strong acid such as, for example, hydrochloric acid to yield 1' di-n-propylcyanacetic crude that the decarboxylating by heating to a temperature between 140 and 190 °c, thereby providing ^ di-n-propylacétonitrile "

the starting materials of formula II are either known products which were cited in the publications, either products obtainable by known methods "

As regards the phase alkylation, implementing reagents will take place by adding, at a temperature between 45° and 55 °c_S n-propoxide sodium in medium or n-propanol to a reaction medium comprising the ester methoxyacetic and n-propyl halide " the alkylation reaction is then conducted at reflux for about three hours -,

the saponification of the ester of di-n-propylcyanacetic crude will occur, in turn, advantageously at a temperature between 70 and 60° °0 during three hours at a rate of 1.25 to 2 moles hydroxide/mole of ester and subsequent acidification will be - carried out, for example, with a hydrochloric acid solution to the j % confectioneries and a somewhat lower temperature to 40 °c_{the O}

In an alternative embodiment, the saponification step is carried out in the presence of a quaternary ammonium such as, e.g., trimethylcetylammonium bromide, benzyltrimethylammonium chloride or lauryltrimethylammonium bromide. quaternary ammonium concentration will vary from 0.1 moles/mole to 0,005 ester moles of di-n-propylcyanacetic, 1a saponification temperature as well as the amount of time needed will vary depending on the amount of quaternary ammonium implementation.

For a concentration of 0.1 moles/quaternary ammonium ester mol, saponification will take place during three hours at 30 °c and for concentration of 0,005 moles/mole of the ester, the operation is performed in one hour to 60 and 65°.

As to the phase of decarboxylation, it will be performed on the di-n-propylcyanacetic crude to a temperature between 190 and 140° °0, preferably between 175° and 190 °c.

According to a variant of this last operation, is decarboxylated acid di-n-octyl propylcyanacetic continuously. After having carried the acid in question at a temperature of 185 - 190 °0 and started the decarboxylation reaction, is carried out a continuous introduction of di-n-propylcyanacetic with simultaneous removal of the carbon dioxide released and di-n-propylacétonitrile formed.

The method of the invention has incontestable advantages relative ' to the processes of the state of the technique mentioned hereinbefore.

First of all, the method of the invention affords the possibility of obtaining high yields of di-n-propylacetonitrile pure, of at least 80 PA with respect to the ester starting methoxyacetic, while with the methods suggested by the state of the technique, could not be determined yields greater than 50 of/with respect to the same starting ester "

In addition,, the method of the invention is much simpler than Marshall's, Brownian et al, or Newman and transporter "named above" e.g., the method of the invention allows the phase alkylation into a single time comprising a single engagement of halide n-propyl and n-propoxide alkali metal "

However, the method of Brownian et al " requires two successive added alkoxide and halide while according to

O the method Newman et al ", the addition of alkoxide and halide take place in three for each product"

the durations of the phases alkylation and saponification are also considerable, in the case of known methods:

at least eight hours ottoman phase alkylation according to method 5 Newman et al ", and twenty-six hours for the phase saponification according to these same authors.

the method of the present invention, on the contrary, the corresponding stages perform alkylation and saponification much more quickly than known methods.

O with respect to the phase of saponification, the time for such operation will be reduced advantageously in the presence of a quaternary ammonium compound, for example trimethylcethylammonium bromide " this quaternary ammonium moreover has the advantage of reducing the risk of hydrolysis of the nitrile of 5 the di-n propylcyanacetic.

Further, the phase of decarboxylation of known methods requires, in addition to an increase in temperature, the adds additional product, §ILO potassium hydroxide, either copper powder "

3 According to the invention, the phase of decarboxylation occurs simply by heating^- the di-n-propylcyanacetic.

Another disadvantage of the methods suggested by the prior, and ^ especially by alkylating the phases in these methods is contemplated at the

>solvent recovery, unreacted reagents and byproducts formed during the reaction "

This recovery quite difficult when using sodium ethoxide/ethanol or sodium methoxide/methanol is facilitated by the use of torque-n-propylate sodium/npropanol, which allows a greater possibility of distillative removal of the halide unreacted n-propyl, ether formed during the reaction and alcohol optionally released by transesterification of the ester methoxyacetic by n-propanol.

All this s-disadvantages the methods suggested by the prior increase amount..de equipment to be used, the hand-d-out * and the expense of energy causing an increase parallel costing "

Among the disadvantages' presented by known methods, the presence of harmful impurities through stages is certainly not the least negligible.

SSO impurities_S present at each step of the process, complicate even more particularly is working thereof, it is necessary to remove them at each step, thereby significantly increasing the manipulations intermediate always expensive industrially.

For example, the methods suggested by the prior contemplate the removal, after phase alkylation, the monoalkylated product and, by means of potassium hydroxide to 10

The phase alkylation contemplated as part of the method of the invention, avoids the intermediate purification of the di-n propylcyanacetic, which may be used in crude form.

Indeed, it has been found that the implementation of alkylating reagents according to the invention, substantially by the introduction of n-propoxide or n-propanol/sodium in a medium formed by the ester of formula II and n-propyl halide, has the advantage that substantially prevent ester formation monopropylcyanacetic which is much greater when - adds the methyl n-propyl ester mixture at ^ n-propoxide methoxyacetic/sodium. In effect, this ester monopropylcyanacetic, will give rise subsequently at valeronitrile particularly annoying that it will be necessary to remove.

Carrying out alkylation reagents, according 1' present invention, diminish very significantly the content of di-n-propylacétonitrile final valeronitrile, this content passing from 3.6 lo about 0.3 to only, according to the invention.

The other hand, the use of n-propoxide sodium/npropanol, according to the invention, were far more advantageous than that of sodium ethoxide/ethanol or sodium methoxide/methanol, advocated by the prior methods.

It has in fact been found that the content of the di-n-propylcyanacetic monopropylcyanacetic crude ester, which duct, subsequently, at valeronitrile, increases and may even vary from 2 to 5 i° if the reflux temperature of the reaction medium is too low at the phase alkylation, which is the case with methanol or ethanol.

Furthermore, it has been found ' that the use of the torque sodium ethoxide/ethanol may give rise to the formation of an insubstantial amount ester ethyl N-propylcyanacetic during phase alkylation, on the order of about 1%.

On the other hand, as aforesaid, the saponi orbit of the di-n propylcyanacetic crude according to the conditions of... him et al, or Marshall's, it is to say by means of potassium hydroxide to 35 i° during sixteen to twenty-six hours leads to a di-n-propylcyanacetic raw material containing 18 to 34 $of an impurity which seems to be an ester of di-n-propylformamidoacetic which is to be removed. In effect, the product does not lead to a di-n-octyl propylaeétonitrile by decarboxylation, but at the di-n-propylacetamide.

Again the method of the present invention avoids this disadvantage and at the same time an intermediate purification of the di-n-propylcyanacetic crude.

In the course of tests conducted in the context of the present invention, it is attempted to combine some characteristic phase of the method of the invention with phases used by previous methods mentioned above.

For example, the phase dialkylation of the method of the invention combined with the step of decarboxylation of di-n-propylcyanacetic by fusion with twice its weight of potassium hydroxide à,85 ^ 190° has a temperature of between 360 °c and, according to the technique of Marshall does provided that 11 The O/degrees di-n-propylacétonitrile with respect to the ester methoxyacetic engaged. In this implementation, most of the di-n-propylcyanacetic has become a di-n-propylacetamide and di-npropylacetic.

It has also provided an alternative method of decarboxylation ml4rshal 1 with the di-n-propylcyana this tick, obtained according to steps of the method of the invention, and two times its weight of sodium hydroxide to 98 the IDegrees " this mixture distilled during two hours fifteen minutes to 370 °c produces just 38.3 % di-n-propylacetonitrile relative to the di-n-propylcyanacetic ngagé O-I

On the other hand, has been distilled off di-n-propylcyanacétate methyl obtained according to steps of the method of the invention, in the presence of potassium hydroxide according to the technique of Brownian et al.

Using twice the weight ester in potassium hydroxide to 97.7 and heating at 380 °c at least during two hours fifteen minutes, but it is realized that 28.4 i° di-n-propylacétonitrile pure with respect to the ester starting methoxyacetic "

The same test, made with the same amount of sodium hydroxide to 98 the I<>, under the same conditions of temperature and time, has given a yield of 44.4 i° di-n-propylacétonitrile with respect to the ester starting methoxyacetic "

It is clear, based on the total results listed above, that the method of this invention provides a significant advantage over on the methods suggested by the prior "

On the other hand, the method of the invention is superior to known and used to prepare di-n-propylacétonitrile, which was discussed previously "

The exemplary, non-limiting, illustrate the invention the following:

EXAMPLE 1

a) di-n-propylcyanacetic

Prepared, first of all, a solution of n-propoxide sodium from - 7.42 grams of sodium (0,322 moles) and 180 ml of anhydrous n-propanol, by heating to light reflux until complete dissolution of sodium "

In a 500 ml flask, equipped with a bulb insertion, a mechanical stirrer, a thermometer and a refrigerant surmounted by a guard, to calcium chloride, introduced 16.95 g of (0,141 moles) of ethyl and cyanacétate 40.69 grams (0.33 moles) of n-propyl bromide " this mixture is heated to 45 °c, then added, slowly and with stirring, the solution of n-propoxide sodiu.m_? prepared previously, by maintaining the temperature of the reaction medium to 50 and 55 °C by a slight external cooling.

At the end of 1^! introducing, in bringing the temperature of the mixture at reflux in thirty minutes and kept there for three hours. Thereafter distilled n-propanol and the distillation is stopped when the temperature of the residual mass reaches 115 °0.

The crude ester obtained in this way is then treated with a solution of 7.5 g of sodium hydroxide in scales in 67.5 ml of water. Placing the mixture into a 250 ml flask surmounted by a refrigerant, and then door slowly the reaction medium to 60 a-70°cc maintains this temperature for ' three hours, then cooled to 50 °c and removed under pressure of 70 mm Hg absolute ethanol formed and the rest of n-propanol. Is cooled to 20 °c the solution thus obtained and the acidified, under stirring, by addition of 26.25 g hydrochloric acid to 36 is maintained, during this operation, the temperature of the reaction mixture below 40 °c by cooling. The stirring is maintained for thirty minutes and then allowed to stand for thirty minutes. The concentrated oily layer of di-n-propylcyanacetic then extracting the aqueous phase with 35 ml of toluene. The extract is added to the toluene di-n-propylcyanaeetic settled followed by washing of the toluene solution, in a separatory funnel, with a solution of 1.5 g of sodium chloride in 14 ml of water.

The concentrated toluene phase is then distilling toluene under atmospheric pressure.

In this way, 25 g of obtained di-n-propylcyanacetic crude.

b) _Di-n propylacétonitrile

In a 100 ml flask, equipped with a thermometer and a refrigerant, introduced 25 g of di-n-propylcyanacetic obtained crude method is disclosed above, and the mixture is heated oil bath at₀

the decarboxylation ' begins to around

of 140 °0. Then the mixture is heated at reflux temperature, it is to say about 160 and 190 °0 °0 within two hours. Maintains this temperature until the end of the off-gas, thereby requiring two hours. Thereafter distilled slowly di-n-propylacétonitrile formed thereby and the fraction is collected and 165 passing between 175 °c. Then made a second distillation.

This manièrej 14.7 g of collected di-n propylacetonitrilec Ρ, Β, ; 170 °0,

Yield 83 sec. i° relative to cyanacétate ethyl engaged, e.g.2 ENV

Preparedexcept di -n propylacétonitrile

a) di-n-octyl propylcyanacetic _Acide

Prepared, first of all, a solution of n-propoxide sodium from 50 grams (2 ATs, g + 10 oF) sodium and 804 grams (1000 ml) of anhydrous n-propanol by heating to 50 and 55 °C for 60 to 90 min.

In a two liter flask, introduced 99.1 grams

(1 moles) of methyl cyanacétate 270.6 gms (2.2 mole) of n-propyl bromide. Under stirring, bringing the mass to 45 - 50⁰ C and, at this temperature, the solution is introduced regularly propanol n-propoxide sodium. This takes of 60 to 75 min,

At the end of the introduction, involves heating the mixture at reflux for three hours. Then distilled n-propanol until reaching 120 and 125 °C in the residual mass. The crude ester obtained is then treated with 500 g of an aqueous solution of sodium hydroxide to 10 with fo and 0.36 g of bromide by cetyltrméthylammonium.

Involves heating the mixture at reflux during one hour, cooled to 50 °c residual alcohols are removed under reduced pressure (50 to 100 mm, mmHg)₀

The resultant solution is cooled and then acidified, without exceeding 40 °c, using 175 g hydrochloric acid to 36 1o_has The mixture is maintained in this way during 30 min, then decanted acid of i-n propylcyanacetic, the lower aqueous layer is extracted by 250 g of toluene. Joining the two organic phases, washing them once with 100 g of purified water and the solvent is removed by distillation under reduced pressure to obtain 154.5 g of di-n-propylcyanacetic crude,

b) di-n-octyl propylacétonitrile

Is transferred into a balloon 250 ml of the obtained crude di-npropylcyanacetic previously and is heated gradually to reflux by removing the last traces of toluene * 1 by means of a Dean-Stark apparatus until a material temperature of 175 to 180 °c, the decarboxylation begins to 140 °c and the reaction is virtually complete after one hour at reflux " the mixture is maintained during a total of two hours at reflux,, mass temperature reaches 205 and 210 °C in the first minutes of reflux and then down and settle to 185 °0_{the O} Then the mixture is distilled at atmospheric pressure to the O

In this manner_Receive collected 102.5 g of di-n-octyl propylacétonitrile₀ Crude product yield: 82 $relative to cyanacétate methyl "pure product yield: 80 $"

EXAMPLE 5

In an enameled container 50:1 introduced 30 kg of di-n-propylcyanacetic " under stirring, heated at reflux to 185 and 190 °C and maintained as such during 15 min. Distilled then di-n-propylacétonitrile formed while continuously supplying 69.4 kg of di-n-propylcyanacetic "

The feed rate is adjusted based on the distillation rate nitrile - while maintaining the temperature of the mass to 185 and 190 °g₀ The introduction lasts about 4.5 hours during which collects 40.9 kg of di-n-propylacétonitrile crude. The distillation is continued by raising gradually the mass temperature up to 206 °c and up to completion of the procedure "this takes six hours during which collects 16,350 kg then again 8,980 kg of di-n-propylacétonitrile raw"

The apparatus is placed under reduced pressure (about 100 mm ïïg) and collected, a new fraction of 1,640 kg of di-n-propylacétonitrile "

In this way, it was achieved 67.87 kg of di-n-propylacétonitrile raw "