IE50863B1 - Process for preparing acetic acid derivatives - Google Patents

Abstract

Di-n-propyl acetic acid is obtained in higher yields by hydrolysing di-n-propyl acetonitrile with concentrated sulphuric acid at an elevated temperature to form di-n-propyl acetamide and then reducing the concentration of the sulphuric acid in the reaction mixture and refluxing it at a generally higher temperature to convert the acetamide into di-n-propyl acetic acid. Recovery of the acid product is advantageously effected by the passage of a steam jet through the reaction mixture, since this enables a purer product to be obtained, in particular a product containing a smaller quantity of valeric acid as impurity.

Description

This invention relates to an improved process for preparing di-n-propyl acetic acid (also known as valproic acid)..

Valproic acid and its alkali and alkaline earth metal salts are disclosed, in British Specification No. 980,279, as having neurotropic properties and in particular anticonvulsive properties which have made valproic acid and especially the sodium salt thereof especially useful in the treatment of epilepsy.

In British Specification No. 1,529,786 there ie disclosed a process for preparing valproic acid comprising the following steps: (1) reacting a lower alkyl cyanacetic acid ester 15 in n-propanol with n-propyl bromide or iodide in the presence of sodium n-propylate to obtain a crude ester; (2) saponifying the crude ester with a 10 to 20% by weight solution of sodium or potassium hydroxide 2° and acidifying the resulting salt with a strong acid to obtain crude di-n-propyl cyanacetic acid; (3) decarboxylating by beating to 140 to 19O°C the crude di-n-propyl cyanacetic acid to form di-n-propyl acetonitrile; (4) hydrolysing the di-n-propyl acetonitrile with to 80% by weight aqueous sulphuric acid at frcm 80 to 140°C to form crude di-n-propyl acetamide; and (5) converting the crude di-n-propyl acetamide into di-n-propyl acetic acid by further reaction with 75 to 80% by weight aqueous sulphuric acid at from 40 to 80°C in the presence of sodium nitrite to cause diazotisation and hydrolysis of the crude di-n-propyl acetamide, the desired di-n-propyl acetic acid being recovered from the reaction mixture.

Step (4) may be represented as follows:- n-CgRj, 'CH-CSN xch-c-nh2 Step (5) may be presented as follows:n-CgH? ' 0 ;CH~C-NH2+NaliO2+H2S<3 n_C3E7 CH-C-OH+N2+H20+NaHSO4 n-Cgl^ However it has been found in practice that this process has some disadvantages. Firstly, it requires the use of sodium nitrite, which is a toxic compound, its LDg0 in rats being 180 mg/kg by the oral route, and which results in the formation of nitrite and nitrate ions which contaminate the desired di-n-propylacetic acid. Secondly,. the presence of valeronitrile as an impurity in the crude di-n-propylacetonitrile leads to the formation of valeric acid which gives rise to a very unpleasant odour in the final product. Finally, the working conditions in a concentrated eulphuric acid medium lower the overall yield of the process.

It is an object of the present invention to provide 30863 f conversion surprisingly gives a better product. This step may be represented 0 / n-CgH? 2H20 n-C3H7 'CH-C-NHx an improved process for producing valproic acid which will avoid the above-mentioned disadvantages and enable the desired product to be obtained in higher yields and with greater purity.

It has been found in accordance with the invention that conversion of the crude di-n-propyl acetamide into di-n-propyl acetic acid does not require the use of sodium nitrite to effect a diazotisation reaction, but can be effected solely by hydrolysis with sulphuric acid having a concentration slightly lower than that employed in hydrolysing the di-n-propyl acetonitrile to form the di-n-propyl acetamide, and that such a yield of the desired as follows: Ή-C-OH + (NH4)2SO4 n-C3H? "2ωυ4 n-C3H? (60%) In addition to the elimination of the nitrite and to the fact that the working conditions are rendered more easy, the process of the invention enables di-n-propyl acetic acid to be obtained which is free from the starting nitrile and, most importantly, from di-n-propylacetamide. .

Thus in accordance with the invention there is provided a process for preparing di-n-propyl acetic acid which.comprises hydrolysing di-n-propyl acetonitrile with 75 to 85% by weight sulphuric acid, preferably about 80%, at from 80 to 120°C, preferably about 100°C, to form di-n-propyl acetamide in the reaction mixture, introducing into the reaction mixture sufficient water to reduce the sulphuric acid concentration to from 55 to 65% by weight, preferably about 60%, and thereafter heating the diluted o reaction mixture under reflux, preferably at 125 to 130 C for from 4 to 6 hours, until conversion of the acetamide to the required di-n-propyl acetic acid has been completed, the required product then being recovered from the reaction mixture.

In a preferred embodiment of the invention, recovery of the di-n-propyl acetic acid from the final reaction mixture is effected by use of a jet of steam. It has been observed that separation by means of steam acts selectively with respect to residual impurities, not only with regard to the residual nitrile and amide but also the valeronitrile and valeric acid of which the content in the end-product may be reduced by half. Furthermore, separation by steam is more advantageous economically than rectification since it requires less costly apparatus.

The beneficial effect of separation by steam on the purity of the di-n-propyl acetic acid product has been verified. In this connection, the following trial has been carried out: An experimental hydrolysis mixture was constituted as follows: Di-n-propyl acetic acid (1 mol) containing 0.35% valeric acid 144 g S0% Sulphuric acid 730 g To this mixture, known quantities of valeric acid were added to obtain concentrations varying from 0.35 to 1% of the acid. This mixture was then submitted to a jet of steam while the volume was maintained constant and the temperature kept at 130°C.· The volume of water required for the separation was 1800 ml/mol of final product so separated. The yield in isolated di-n-propyl acetic acid was practically quantitative. Decantation at roomtemperature was undertaken together with drying on sodium sulphate. Analytical verification of the quantity of valeric acid wae then carried out.

The results are listed in the following Tables A and B.

In Table A the results are given of four trials in which different starting quantities of valeric acid were used.

In Table B, the results are given of one continuous operation in which the starting quantity of valeric acid was 1%. It was thus possible to follow the evolution of the quantity of valeric acid in the various successive fractions of di-n-propyl acetic acid obtained after separation with steam.

TABLE A •.Trial :No. Starting content in valeric acid (%) Quantity of valeric acid : in the di-n-propyl acetic, acid obtained using steam' (%) : 1 0.35 0.2 : : 2 0.60 0.3 : : 3 0.80 0.4 : : 4 1.00 0.5 : TABLE B Starting quantity of valeric acid in the crude di-npropyl acetic acid before separation with steam : 1% = 1.44 g : Successive . fractions Weight of fraction (g) the : Quantity of valeric acid in the di-npropyl acetic acid obtained (%) Corresponding; weight in valeric acid -(g) : : I 36 : 0.9 0.324 : II 34 0.6 0.204 ' · : : III 42 0.2 0.084 : IV 32 0.1 0.032 : : Total 144 0.644 : Recovery of valeric acid : 44.72% These results show that the separation of di-n-propyl acetic acid using a jet of steam in accordance with a preferred embodiment of the invention lowers the quantity of valeric acid by about 50%.

This advantage is of considerable importance in view of the very unpleasant odour which even small quantities of valeric acid can impart to the final product.

The following Examples illustrate the invention. 5086 3 - 7 EXAMPLE 1 Preparation of di-n-propyl acetic acid Into a 1000 ml flask fitted with a stirrer, a thermometer, a dropping-funnel which can be replaced by a dip tube and a vertical reflux condenser, were introduced 72 g of distilled water. Then 478 g of 92% sulphuric acid were slowly introduced with stirring, the temperature being kept below 60°C. 125.2 g (1 mol) of di-n-propyl acetonitrile were then added in one addition and the temperature was increased to 100°C.

This temperature was maintained for 1 hour which was the time required to ensure that the nitrile was almost completely hydrolyzed to amide. 185 g of distilled water were then added', also in a single addition, to bring the sulphuric acid concentration to 60%.

The resulting reaction mixture was brought to reflux (125-130°C) and maintained under reflux for 5 hours. The condenser was then converted to an apparatus for distilling at atmospheric pressure and the desired product was separated out by introducing steam through a dip tube. This operation lasted 2J hours which was the length of time required to terminate the demixing in the distillate and corresponded to the use of 1750 g of water for the separation. The .operation was carried, out at a constant volume ir. the flask, which increased productivity and enabled hydrolysis to be completed. The two layers so formed were cleanly separated. As a result, the volume of the organic phase collected could be limited by drawing off tne aqueous phase at intervals and the use of an extraction solvent could be avoided.

The organic phase was then dried under vacuum (20 mm Hg, 20°C) by azeotropy.

In this manner, there were obtained 138.5 g of di-n-propyl acetic acid which could be further purified by flash distillation. Yield : 96.2%.

EXAMPLE 2 Preparation of di-n-propyl acetic acid 0.657 kg of distilled water was introduced into an enamelled reactor fitted with a 200 1 flask, reflux equipment, a stirrer and a bottom valve, the flask 2 receiving steam under 6 kg/cm pressure.

While stirring and maintaining the temperature at 50-60°C, 2.085 1 (3.753 kg) of 94% sulphuric acid were added.

After 15 minutes of stirring, the concentration of the acid was controlled at 80 - 1% by weight. The temperature was then brought to 100°C and 1 kg of di-npropyl acetonitrile was introduced. The reaction was exothermic and the temperature was maintained at 100°C by circulating water. After the introduction was terminated, the temperature was maintainedfor 1 hour with stirring.

Then, 1.470 kg of distilled water were added while the temperature was maintained by slight heating to obtain a 60% concentration of sulphuric acid. The resulting reaction mixture was then heated to 125-128°C to obtain reflux which was continued for 6 hours. The reaction mixture was then cooled to about 30°C, stirring was stopped and the mixture allowed to decant for 30 minutes whereupon lower sulphuric mother-liquors were drawn off, which represented 3.5 1^, i.e. about 5 kg. These motherliquors bad an acid titration of about 59% sulphuric acid. The organic layer was then washed at about 30°C for 30 minutes by means of 1.333 kg of distilled water. After decantation for 30 minutes, the lower aqueous phase (1.4 kg) was drawn off. The water/di-npropyl acetic acid mixture was then also drawn off to be filtered thus providing di-n-propyl acetic acid.

Finally the organic phase comprising di-n-propyl acetic acid with about 1% water was drawn off.

In this manner, 1.12 kg of di-n-propyl acetic acid were obtained, representing a yield of 97-98%.

Claims (7)

1. A process for preparing di-n-propyl acetic acid, which comprises hydrolysing di-n-propyl acetonitrile with 75 to 85% by weight sulphuric acid at irom 80 to 120°C to form di-n-propyl acetamide in the resulting reaction mixture, introducing into said reaction mixture sufficient water to reduce the sulphuric acid concentration to from 55 to 65% by weight, and thereafter heating the diluted reaction mixture under reflux until conversion of the di-n-propyl acetamide to di-n-propyl acetic acid has been completed, the di-n-propyl acetic acid then being recovered from the reaction mixture.

2. A process according to claim 1, wherein the hydrolysis is effected with substantially 80% by weight sulphuric acid at substantially 100°C.

3. A process according to claim 1 or 2, wherein the sulphuric acid concentration is reduced to substantially 60% by weight.

4. A process according to claim 1, 2 or 3, wherein the diluted reaction mixture is refluxed at 125 to 130°C for 4 to 6 hours.

5. A process according to claim 1, 2, 3 or 4, wherein recovery of the di-n-propyl acetic acid from the reaction mixture is effected by use of a jet of steam.

6. A process for preparing di-n-propyl acetic acid, substantially as described in either of the foregoing Examples.

7. Di-n-propyl acetic acid whenever prepared by the process claimed in any preceding claim.