DD215533A1 - PROCESS FOR THE PREPARATION OF NEW ALKALI AND ERDALCALISALES OF DI-N-PROPYL ACIDIC ACID - Google Patents

Abstract

In the A, a salt of the di-n-propylacetic acid of the formula II is designated, in which Me represents an alkali metal ion or represents 1/2 of the alkaline earth metal ion, B is di-n-propylacetic acid of the formula (II). n-propylacetic acid and m and n indicate different molar numbers, in which n is a part of m in the limits of> 0.05 to <1.0 m, can be prepared by either a) m moles of an alkali or alkaline earth metal salt of the general formula II with n moles of di-n-propylacetic acid, where m and n have the above meanings, or b) di-n-propylacetic acid in a quantity greater than that required for neutralization, namely with more than 5% and less than 100% excess, with an alkali hydroxide or carbonate or an alkaline earth, hydroxide or carbonate.

Description

Title of the invention.

Process for the preparation of new alkali and alkaline earth salts of di-n-propylacetic acid

Field of application of the invention

The invention relates to the preparation of new alkali metal and alkaline earth metal salts of di-n-propylacetic acid of the general formula

m [A] · .n [B] I

in the A is a salt of di-n-propylacetic acid of the formula

CH - COO Me II

o ** GHrJ - CHq

CH ₃ - CH ₂ - CH ₂

in which Me stands for an alkali metal ion or for 72 alkaline earth metals, B denotes di-n-propylacetic acid and m and η indicate different molar numbers, in which η is a part of m within the limits of y 0.05 m to \ Λ , 0 m is.

The novel salts can be used in the medicamentous therapy of epilepsies. They can also be used advantageously as starting material for the preparation of pure salts of the general formula II which are composed of equivalent acid and alkali or alkaline earth parts

^: '. - ² -. '''''·.'. , . '. ·

be used.

Characteristic of the known technical solutions

There are known salts of general formula II. Thus, in DD-PS 129 776 in Example 1 and Example 4, the preparation of the sodium salt of 'di-n ~ propylacetic acid from approximately equivalent amounts of UaOH and di-n-propylacetic acid described in Spanish Patent 380 9O3 is a method for producing the rubidium salt from RbOH and di-n-propylacetic acid. U.S. Patent 3,814,812 discloses a method of recovering calcium. Bis- (di-n4-propyl acetate) from calcium oxide and di-n-propylacetic acid in water. ;

The known salts of the general Pormel II adhere to various disadvantages, since they have an unfortunate effect on the production, storage, processing and use. Thus, the sodium salt is highly hygroscopic and deliquesces in the air within minutes. It thus provides for its production and processing special conditions whose realization is complex on an industrial scale.

Another disadvantage is the poor solubility of such salts in common organic solvents such as toluene, acetone, Eaaigester, chloroform and others, whereby purification operations, which also serve the separation of residues still present in the salt of alkaline starting materials, are difficult. ,

In DE-OS 2,850,4Oi) is particularly pointed to such difficulties and to avoid alkali in

· '' '. - 3 - ''. ' '' '' '' · '"

Sodium salt proposed to carry out the preparation of sodium salts of general formula II so that instead of the equivalent amount of sodium hydroxide only 97 - used 98 % thereof, which otherwise also corresponds to the procedure in Example 1 and Example 4 of DD-PS 129 776.

Pur the Calciuinsalz of the general formula II is known from the older literature (Fürth, Monatshefte f. Chemie S> (1889) ,. p 320-322) an abnormal Lösungaverhalten known daa therein beateht that the solubility in water at 0 C ⁰ is largest and decreases with increasing temperature and at 80 ⁰ G is only about 1.6 % »This fact is in some contradiction to the teachings disclosed in US-PS 3,814,812 teaching a calcium salt in water. And leaves justified doubts about the available yield. Therefore, attempts to reproduce also gave deviating results and resulted in addition to a large amounts in parts, insoluble in hot water, gray-colored impure residue of unspecified kind to a maximum of 45 $ yield of calcium, which this method in addition to its high volume cost and economic is ungünatig. -

In order to avoid difficulties in salt formation, the practical application of di-n-propylacetic acid as a drug has already been preceded by the therapeutic use of the acid in non-salt-bound form. In the case of the use of the Din-propyleaaigaäure, which is an oily, waaaerunlu'8liche liquid, thereby creating other problems, which consist in that a special encapsulation with

 / ''; : '

specific Yerlapaelungstechnik iat required, the resilience of the Kapael material to di-η-propyl acetic acid plays a significant role. Because of the excellent solubility properties of this acid, which is a very good solvent due to its acidic, oily nature as a branched chain fatty acid, the choice of suitable capsule material and additional fillers has been limited. With unsuitable material under air, light and temperature influences it can lead to qualitative changes and also to discolorations.

Another approach to avoid the disadvantages listed has been described in recent literature (BB-PS 884 848) with the preparation of "dimeric" salts of gleichmolaren portions of a salt of the general formula II and di-npropyleigsigsäure · It is assumed hereby assuming that a "dimeric" product of the formula

^ O * ..... HO. CH ₀ -CH ₀ -CH. .. '

CH-C :, ·, C-GH TII

/ s \. y - "\

CH ₂ -CH ₂ -CH ₂ OMe ..... O ^ CH ₂ -CH ₂ -CH ₃

(Me = sodium or ^1/2 calcium) arises * These "dimeric" fabrics have a high proportion of percentage of attached di-n-propylacetic acid, "which in the case of the sodium salt 46.45 fo, in the case of the calcium salt 46,90% the molecular weight is.

This high content of di-n-propylacetic acid naturally gives these salts a greasy character and has an unfavorable effect on the flowability or mechanical stress (crushing, grinding, grinding, sieving, pressing and the like), so that advantages such as purifications by Urakristaliisationen thereby

; '. , - 5 -,. , . ·; Be '''' compromised _again: \ -.

Object of the invention

The invention makes it possible to prepare novel salts of di-n-propylacetic acid, which differ advantageously both in terms of their preparation and purification capability and in terms of mechanical strength in the further processing of previously known solutions.

The invention makes it possible, in contrast to previous formulations, to prepare novel salts of di-n-propylacetic acid which are variable in the limits specified according to the invention with respect to their content of "free, non-ionically bound" di-η-propylacetic acid. As any examples are sodium salts with 10 % _t 20 '%, 21%, 32.% etc. or calcium salts with 10 "%, 16 %, 30 % or 33 % content of non-ionic bound di-npropylessigsäure called, without further variants Each of these ratios is experimentally smoothly reproducible.

i. '' · The new salts show properties that are important for the.gale-,

nische further processing are favorable. They are easy to handle as amorphous or finely crystalline powders, free-flowing, millable, etc., which applies in particular to those salts whose proportion of non-ionically bound di-n-propylacetic acid is between 5 and 35 % . At the same time with this content of free di-npro pylessigsäure sufficient protection against excessive hygroscopy, as it is known for example of sodium di-n-propyl acetate connected.

:. ';. - 6. ' - ^:; - /. .:. , '; , λ ·.

Thus, a sodium salt of general formula I with 32% of structural part B within 8 hours at a relative humidity of 54 % hardly increases in weight even after several days by absorption of water.

The biocompatibility and the associated pharmacokinetic parameters of the salts obtainable according to the invention also show statistically significant differences compared with the known sodium salt of di-n-propylacetic acid. Clinically, a calcium salt with 30% content of structural part B has proven equally effective in application against epilepsies as known commercial preparations.

(y '. ''. , '. ''

obligations.

Explanation of the essence of the invention

The object of the invention is to develop processes for the preparation of novel salts of di-n-propylacetic acid of the general formula I which are technically easy to carry out and which give salts which are less problematic in further processing than previously known salts.

According to the invention this is achieved in that either a) a known alkali or Erdälkalisalz the di-npropylacetic acid of general formula II with di-npropylesaigsäure according to the equation

m [A] + η [B] -> I

where A, B, in and η have the same meaning as above, or

b) Di-n-propylacetic acid in a quantity greater than that required for IT re-balancing, namely with more than

      , - 7 -. y. .... .- .. ''

and less than 100 % excess with an alkali hydroxide or alkali carbonate or a Erdalkalipxid, hydroxide or -bonbonat.

A special Ausfühjcungsform of the invention is that a salt of the general formula I prepared according to the invention is converted by reaction with a further amount of di-n-propylacetic acid in a salt of general formula I, in which the structural portion B is greater than in that for this starting salt of general formula I employed without exceeding the limit specified in formula I. , ·. ,,; , ''. ' -. ; '

Conversely, a salt of the general formula I prepared according to the invention can be converted into a salt of the general formula I by reaction with a further amount of an alkali hydroxide or carbonates or alkaline earth metal oxide, hydroxides or carbonates, in which the structural part B is smaller than in the formula used for this "concentrating" process starting salt of general formula I, without falling below the specified in formula I lower limit.

In order to avoid interfering Umsalzeffekten it goes without saying that for such a "concentrating" reaction the same alkali or "alkaline earth metal ions in the applicable alkalis or alkaline earths contained in the Ausgangsasalz used in this reaction of the general formula I, ie For example, sodium hydroxide in calculated amount for a sodium salt of the general formula I.

Suitable solvents for the reactions according to the invention are hydrocarbons such as hexane, aromatics such as benzene and toluene, esters such as ethyl acetate, ketones such as acetone or methyl ethyl ketone and halohydrocarbons such as chloroform The solvents may also be present in admixture with water.

The processes according to the invention are expediently carried out at room temperature or at elevated temperature up to the boiling point of the solvent or solvent mixture.

The salts prepared according to the invention are colorless, crystalline substances which, with increasing content of structural part B, have particularly well-formed, large crystals. They dissolve in common organic solvents such as toluene, acetone, esters and others, wherein the solubility at room temperature increases sharply with increasing proportion of the structural part B.

The salts obtainable according to the invention react weakly acidic, whereby the pH shifts more strongly to the acidic range if higher proportions of B are present in the salt.

The success of the process according to the invention is surprising. Due to the above-described stoichiometric composition of the known neutral salts of di-n-propylacetic acid and the so-called "dimeric" compounds according to Belgian Pat. No. 884,848, the broad variability of the salts described in terms of their material composition was not to be expected in any way.

Auaführungobeispiele

Example 1>.

72 g of di-n-propylacetic acid (0.5 mol) and 23 g of calcined < soda (0.217 mol) are refluxed with stirring in 300 ml of acetone for β hours. On an undissolved portion (4g) is sucked hot. The naked filtrate is concentrated to dryness while distilling off the acetone, leaving a residue which is poor in Y.sup. + In 90 g. When hot, the syrupy mass is dissolved in 200 ml of toluene, filtered blank and in a flowing water bath at 12 ⁰ C bath temperature for crystallization, left to stand. After standing for several hours, the crystallized salt is filtered off and the PiIterrückstand washed twice with 30 ml of toluene. After drying in vacuo at 50 ⁰ G to obtain 63 g of colorless, shiny crystals having a content of 20 % di-npropylacetic acid in potentiometriacher determination in addition to 79.5:% content of sodium di-n-propylaeetat and residual moisture.

Example 2.

144 g of di-n-propylacetic acid (1 mol) are boiled with 40 g of calcined soda (0.377 mol) in 740 ml of toluene for 3 hours while stirring at reflux. The hot solution is filtered off from undissolved material and then crystallized for several hours in a flowing water bath. After suctioning off the salt, washing with 100 ml of toluene and drying to constant weight, 107 g of a salt with a content of 21 % of di-n-propylacetic acid and 79 % of sodium di-n-propyl acetate are obtained. ,

- 10 .-. Example 3

144 g of di-n-propylacetic acid (1 mol) and 36 g of caustic soda (0.9 mol) in cookies are stirred in 1000 ml of toluene for 2 hours at room temperature. After only 30 minutes, the caustic soda is largely dissolved and reacted. After stirring for two hours, the waxy, turbid, opalescent reaction mixture is sucked clean over a mold G 4. The filtrate is left for 3 hours at flowing water cooling at a bath temperature of 12 ⁰ C the crystallization · The abundant, resulting crystals are filtered off on a Pilternutsche, the Filterrückatand washed twice with 100 ml of toluene and dann.im vacuum at 50 ⁰ C dried "Man receives 150 g of a dry crystal powder with a content of sodium di-n-propyl acetate of 89 % and a content of non-ionically bound di-n-propylacetic acid of 10 % _a

Example 4

.144 g of di-n-propylacetic acid (1 mol) are boiled with 50 g (0.47 mol) of sodium carbonate in 700 ml of toluene for 2.5 hours in an oil bath · with recirculation cooling and stirring. From a remaining undissolved residue (about 10 g) is filtered off hot. By cooling to .5 ⁰ C, the solution is brought to crystallization. After standing for three hours, it is filtered off with suction, the filter residue is washed with 100 ml of toluene and dried, in vacuo. 50 ^° C. 161 g of a salt are obtained with 81 %. Sodium di-n-propyl acetate and 18 % di-n-propylacetic acid,

Umkristallisationi 100 g of the above salt are dissolved with heating on a steam bath in 400 ml of toluene The solution provides heißfiltrierte on cooling to 5 ⁰ C 90 g

, , .. - ir -. ·: ·

of a crystallizate containing 81% of sodium di-propyl acetate and of 18% of di-η-propyl-acetic acid.

Example 5:

144 '' g of di-n-propylacetic acid (1 mol) and 35 g of soda (0.33 mol) are boiled in 600 ml of acetone with stirring for 5 hours and filtered hot. The filtrate is concentrated in a water pump vacuum at room temperature until, until abundant crystallization begins. It is then cooled to 12 ⁰ C for several hours and the crystals are filtered off with suction, which is washed with 100 ml of toluene. After drying, 122 g of a salt containing 66 % of sodium di-n-propyl acetate, 33% of di-n-propylacetic acid and 1 % residual moisture,

Example 6

40 g of di-n-propylessigstlure (0.28 mol) are stirred with 5.5 g of a 97 /> calcium oxide (ca, 0.098 mol) in 75 ml of toluene and 50 ml of water at room temperature and 30 minutes in an oil bath to reflux heated. The reaction solution is filtered hot and leaves no weighable residue, Now the aqueous lower layer is separated (50 ml). The upper toluene layer is left in a flowing water bath for several hours of crystallization. After filtering off with suction, washing with 30 ml of toluene and drying, 24 g of a white, well-crystalline salt are obtained with the following content:

65 / i calcium bis-idi-n-propyl acetate) 33 % di-n-propylacetic acid

2 % water of crystallization

_ IO _

Example 7. , ·.

An analogous procedure as in Example 6 using 30 g of di-n-propylessiga acid (about 0.21 mol) to 5.5 g of a 97% solution (about 0.098 mol) leads to 25 g of a salt having the following composition: , ,

68 % Galcium bis-idi-n-propyl acetate) 30 % Di-n-propylacetic acid -2 % water of crystallization.

Example 8.

The same approach as in Example 7, but with the sole use of toluene, results in yield and after the composition of the salt to a similar result

Example 9 ^:

112 g of di-n-propylacetic acid (ca. 0.8 mol) are stirred in 300 DiI toluene with 22 g of a 97 ^ ig ^e n CaO. The mixture is boiled for 30 minutes and filtered while hot. In the bare Piltrat now 100 ml of water are stirred and the mixture was cooled to 12 ⁰ C with stirring. After three hours of crystallization 'is filtered. The resulting salt is washed with 100 ml of toluene and dried, yield: 121 g.

The composition is the same as given in Example 7. ,

Recrystallization: 120 g of the resulting salt are dissolved in 300 ml of toluene on the steam bath hot, blank filtered and the filtrate mixed with 100 ml of water. Under

• - 13 -. -. '·. Λ

Stirring and cooling crystallize 115 g of a salt containing 30 ^ non-ionically bound di-η-propylessigsänre.

Example 10

144 g (1 mole) of di-n-propylacetic acid are dissolved in 560 ml of aqueous, 75% acetone. In this solution, 22 g of CaO are stirred, which dissolve quickly largely. The mixture is boiled for 30 minutes on the steam bath and vacuumed with a little dissolvable water is cooled in the flowing water bath. The abundant crystals are filtered off with suction, washed with 100 ml of a 75% aqueous acetone and dried. Yield: 142 g. Content of non-ionically bound di-n-propylacetic acid: 30 ) ΐ> »

Example 11

50.g of a salt obtained according to Example 9 are heated in 200 ml of toluene together with 1.5 g of CaO for 30 minutes with stirring and then the solution is blank filtered. 2Jach cooling to 12 ⁰ C crystallized from a salt having a content of non-ionic bound propyleasigsäure of 16% after drying "

Claims (5)

, , , - Address H.Patent. ' 1. ancestor for the preparation of new alkali and alkaline earth al ζ β of di-n-propylessigsüure the general formula m [A] · η [B] I in the A is a salt of di-n-propylacetic acid of the formula ; CH ₃ - CH ₂ -, CH ₂ ^X CH - COOMe II -; ' CH ₃ --- CH ₂ - CH ₂ .... in which Me is an alkali metal ion or 72 Brdalkalimetallion, B di-n-propylacetic acid and m and η indicate different molar numbers, in which η is a part of m in the limits of) 0.05 to <C 1.0 m, characterized in that either. . a) in mol einea alkali or .Erdalkalisalzes the general formula II with η mol di-n-propylacetic acid, wherein in and η have the above meaning, or b) Di-n-propyles3ig8äure in an amount larger than *, are reacted for neutralization-necessary amount, carbonate or namely with more than 5% and less than 100 fo excess, with an alkali metal or an alkaline earth hydroxide or carbonate. / 2. The method according to item 1, characterized in that a salt of the general formula I with a lower content of Bm.it di-n-propylacetic acid to a salt of the general formula I with a higher content of B , implements. . ' . ' 3. The method according to item 1, characterized in that one salt of the general formula I with eineta higher content of B with a Alky! Hydroxide or carbonate or an alkaline earth, hydroxide or -car-carbonate to a salt of the general Formula I with lower content of B reacted. 4. The method according to the items Γ to 3, characterized in that the reactions in solvents, for example, Kohlenwaaaeratoffen such as hexane, aromatics such as toluene or benzene, esters such as Essigaäureäthyleater, ketones such as acetone or methyl ethyl ketone or halogen · kohlenv / aaaeratoffen as Chloroform and optionally in the presence of water, 5. The method according to the points 1 bi3 4, characterized in that one works in a temperature range of 0 ⁰ C to the boiling temperature of the solvent used or Lösungsamittelgemiache.