LU83148A1 - PROCESS FOR THE PREPARATION OF ACETIC ACID DERIVATIVES - Google Patents

Description

*

DESCRIPTIVE MEMORY filed in support of an INVENTION PATENT application

formed by

SANOFI

40, Avenue George V - 75008 PARIS, France for

PROCESS FOR THE PREPARATION OF ACETIC ACID DERIVATIVES Inventors: Michel CHIGNAC, Claude GRAIN and Charles PIGEROL

The present invention relates to an improved process for the preparation of di-n-propylacetic acid (also known as valproic acid). .

We have described in the B.S.M. French No. 2442 M the neurotropic properties 5 and in particular the anticonvulsant properties of valproic acid, its alkali metal salts and its alkaline earth metal salts. Valproic acid and more particularly its sodium salt have thus been found to be particularly useful in the treatment of epilepsy.

In the Luxembourg patent N ° 77 * 305 a process for the preparation of valproic acid has been described comprising the following steps: * '' (1) reaction of a lower alkyl ester of cyanacetic acid in n - propanol with n-propyl bromide or iodide in the presence of sodium n-propylate to obtain an ester in crude form (2) saponification of the crude ester with a solution of 10 to 2% by weight of 15 sodium or potassium hydroxide and acidification of the resulting salt with a strong acid to obtain di-n-propylcyanacetic acid / mwltllll '...............

"I r - 2 - (3) decarboxylation of di-n-propylcyanacetic acid by heating to 190 ° C to form di-n-propylacetonitrile.

(½) hydrolysis of di-n-propylacetonitrile with sulfuric acid. 75 to 80/6 by weight at a temperature of 80 ° C to 1 ** 0 ° C to form the crude 5-di-n-propylacetamide; and (5) transformation of the crude di-n-propylacetamide into di-n-propylacetic acid by reaction with sulfuric acid at 75 to 8 <$ at a temperature of kO ° C to 80 ° C in the presence of nitrite of sodium to cause the diazotization and hydrolysis of the crude di-n-propylacetamide, the di-n-propylacetic acid being subsequently isolated from the reaction medium.

Step (4) can be represented as follows: “" ° 3H7 \ HO “" VfX ° CH-0.H ---> CH-C-NH, 15 ^ n-Cf / Step (5) can be schematized as follows: n “° 3H7 \ ^ CH-C-NH2 + NaN02 + H2S0 ^ C 20“ * ° 3Η7 \ ° ^ CH-C-0H + N. + H_0 + NaHS0, ✓ 2 2 hn "G3H7

In practice, however, it has been found that this method has certain disadvantages. First, it involves the use of sociunit nitrite. toxic compound, its IL ^ q in the oral rat being 180 mg / kg.

In addition, this use of sodium nitrite leads in the final product to the presence of nitrites and nitrates ions which affect the purity of this product. Secondly, the presence of valeronitrile as an impurity ± = z ~ ^ j 30 di-n-propylacetonitrile contributes to a very unpleasant odor of concentrated furic grc- // - 3 - affect both the yield and the productivity of the process.

It is therefore an object of the present invention to provide an improved process for the preparation of valproic acid with a view to eliminating these disadvantages and obtaining the desired product with higher yields and greater purity.

It has now been found, according to the invention, that the transformation of crude di-n- * propylacetamide to di-n-propylacetic acid does not require the use of sodium nitrite to cause a diazotization reaction but can be carried out simply by continuing the hydrolysis in sulfuric acid medium with a concentration slightly lower than that used during the hydrolysis of di-n-propylacetonitrile to form di-n-propyl-acetamide, this transformation providing, surprisingly, a better yield in desired product.

15 This step can be represented as follows: 'û- ° 5ÏÏ7 \ ° 2H ο ° 2 CH-C-NEL ---> 2 CE-C-OE + (NE.) _ S0, y 2 H in / ^ 2 b 20 * a »C3y 2 * n-C3ïï? / (60 *)

Besides the elimination of nitrite and the fact that the operating conditions k. · 'Are thus lightened, the process of the invention makes it possible to obtain di-n-propylacetic acid free of starting nitrile and, which is more im-25 bearing, free of di-n-propylacetamide.

Thus the process of the invention for the preparation of di-n-propylacetic acid consists in hydrolyzing di-n-propylacetonitrile with sulfuric acid at 75 to 80 * by weight, preferably about 80 *, at a temperature between 80 and 120 ° C, preferably at about 100 ° C, 30 to form the di-n-propylacetamide in the reaction medium to be introduced into this reaction medium an amount of water sufficient to lower the concentration of sulfuric acid to 55 to by weight, preferably to about 60 ° and to continue heating the reflux of the diluted reaction medium, preferably at 125 to 130 ° C for k to 6 hours at 35 until complete conversion of the amide to acid di -n-propylacetic / / "- if -% the desired compound being subsequently isolated from the reaction mixture.

According to a preferred implementation of the invention, the di-n-propylacetic acid is recovered from the final reaction medium by steam stripping.

5 It has thus been found that this steam entrainment plays a selective role with respect to residual impurities and, in particular, not only of residual nitrile and amide, but also of valeronitrile and valeric acid, of which the content can be halved.

In addition, steam entrainment is preferable to rectification 10 because it involves less investment and represents an advantage O,. .

economic.

The beneficial effect provided by the steam entrainment on the purity of di-n-propylacetic acid has been verified.

To this end, the following test was carried out: • An experimental end-of-hydrolysis medium is reconstituted as follows:

Di-n-propylacetic acid l ¥ f g (1 mole) with valeric acid content = $ 0.35

Sulfuric acid 730 g 20 to 60 $ To this medium, we add, for the purposes of the experiment, known quantities, ··· (of valeric acid, so as to bring its concentration to various values, ranging from 0 .35 to $ 1.

This medium is subjected to steam entrainment, keeping the volume constant and its temperature at 130 ° C. The volume of water required for training is 1800 cm ^ / mole entrained. The yield of isolated di-n-propylacetic acid is practically quantitative.

Decantation is then carried out at ambient temperature and drying over sodium sulphate and the content of valeric acid is checked analytically.

The results are collated in Tables A and B below.

• Table A gives, for four tests, for variable initial contents of valeric acid, the corresponding final contents. ,

Table B allows, on the same test, corresponding to an ini- / - 5 - valeric acid content of the product collected by entrainment ·

TABLE A

• Trial | Initial content of [Valeric acid content of N0 | valeric acid ($) \ di-n-propylacetic acid 5] \] collected by entrainment ($)]; 1; 0.35; o, 2; : 2: 0.60: 0.3! 3! o, 8o; οΛ î: 4 1.00: 0.5: O ............... ......

i

10 TABLE B

Initial valeric acid content of crude di-n-propylacetic acid before steam entrainment: $ 1 = 1, Mlg - 6 -

In a 1000 ml flask, equipped with a stirrer, a thermometer, an introduction bulb replaceable by dip tube and a right reflux condenser which can be modified by distillation at atmospheric pressure, kept in a controlled bath by thermostat, 72 g of purified water are placed 5 and then slowly introduced with stirring V78 g of sulfuric acid 923 ", limiting the temperature to 60 ° C.

125.2 g of di-n-propylacetonitrile (Vmole) are then introduced at one time, the temperature is brought to 100 ° C. and maintained there for 1 hour, at the end of which the hydrolysis of the nitrile into amide is practical. -vs-. 10 total.

185 g of purified water are also introduced at once, bringing the sulfuric acid concentration to 6 ($. The mixture is brought to reflux: (125-130 ° C.) and the reflux is maintained for 5 hours.

The condensation system is then modified in a distillation apparatus 15 at atmospheric pressure, and the entrainment is carried out by introduction of steam by the plunger. We continue for 2 1/2 hours, which corresponds to the cessation of demixing in the distillate, and a consumption of training water of 1750 g.

In this respect, the operation is preferably carried out at a constant volume in the reactor, which improves the productivity and makes it possible to complete the hydrolysis. The decantation is perfectly clean, which makes it possible to limit the volume of organic phase collected, by carrying out discontinuous withdrawals of the aqueous phase and to avoid the use of an extraction solvent.

The organic phase is dried under vacuum by azeotropy under vacuum (20 mm Hg, 25 ° C). In this way, 138.5 g of di-n-propylacetic acid are collected (yield $ 96.2), which can still be purified by flash distillation.

EXAMPLE 2

Preparation of di-n-propylacetic acid

In an enamelled reactor, equipped with a 200-liter gauging flask in OJ-load, a glass superstructure allowing reflux, an agitator and a bottom valve, receiving pressurized water vapor 6 kg / cm ^, 0.657 kg of purified water is loaded, then stirring and maintaining- ____J_ Ί _! ____ '_i_____ 5 P-Λ ^ Λ0Γ- 1-d ____ / -r ----- Λ J » . ____ - 7 -

After 15 minutes of stirring, the acid concentration is checked, which must be 80-1 $ by weight. The temperature is then brought to 10 ° C., and 1 kg of di-n-propylacetonitrile is introduced, by controlling the reaction exothermicity by circulation of water in the jacket of the reactor, so as to maintain the temperature at 100 ° C.

At the end of the introduction, the temperature and the agitation are maintained for 1 hour, then 1.70 kg of purified water are added, while still maintaining the temperature by slight heating, which increases * the sulfuric acid concentration to 6C $.

^ 10 Then heated to 125-128 ° C to bring to reflux, which is maintained for 6 hours.

It is cooled to approximately 30 ° C. and the stirring is stopped, and it is left to settle for 30 minutes, then the lower sulfuric mother liquors, which represent 3.5 liters, or approximately 5 kg, are drawn off via in-15 through a glass balloon serving as a viewfinder. These mother liquors have an acidimetric titer close to $ 59, expressed as sulfuric acid ·

It is then washed at approximately 30 ° C. for 30 minutes using 1.333 kg of purified water, it is decanted for OJ minutes and the lower aqueous phase is drawn off (1 * 1 · kg), then the phlegms <& 'variable importance ) for their filtration to recover the di-n-propylacetic acid, and finally, the organic phase constituted by di-n-propylacetic acid at Λ% water

Kj around

In this way, 1.12 kg of di-n-propylacetic acid are obtained, which represents a yield of $ 97-98. /. (1 / "

Claims (5)

1. Process for the preparation of di-n-propylacetic acid, characterized in that the di-n-propylacetonitrile is hydrolyzed with sulfuric acid at 75 to 85 $ by weight at a temperature of 8θ ° to 120 ° C 5 to form the di-n-propylacetamide in the resulting reaction medium, is introduced into said reaction medium an amount of water sufficient to ♦ ♦ reduce the sulfuric acid concentration to 55 to 6590 by weight and then heated to reflux the diluted reaction medium until complete transformation of the di-n-propylacetamide into acid. ^ 10 di-n-propylac etic, this acid being subsequently isolated from the reaction medium. 2. Method according to Claim 1, characterized in that the hydrolysis is carried out with sulfuric acid at 80 # and at a temperature of 100 ° G. 3. Method according to Claim 1 or 2 characterized in that the concentration of sulfuric acid is reduced to 60 # by weight. k. Process according to Claim 1, 2 or 3 characterized in that the diluted reaction medium is heated at reflux at 125 to 130 ° C for k to 6 hours. 5. Method according to Claim 1, 2, 3 or characterized in that the isolation of the di-n-propylacetic acid from the reaction medium is carried out by means of a steam entrainment. 6. Di-n-propylacetic acid obtained according to any one of Claims 1 to 5. p <- r: -r * _ / ...--------- Γ- 'V'Vcc. dvr; l -—. 0. -te ..... .1 ..... 1 / - ^ ‘· -s; _.......AT...... - ; ·: * · ^ R- _____: A ...... 1> <. - C · i; 3t n