DD215532A1 - PROCESS FOR PREPARING CALCIUM BIS- (DI-N-PROPYL ACETATE) - Google Patents

Abstract

The invention relates to a process for the preparation of calcium bis (di-n-propyl acetate) (I), which is preferably used in human medicine in the drug therapy of epilepsy. The task of an economical method for the production of v. I to develop in high purity and good yield, is achieved by I by salification of alkali metal salts of di-n-propylessigsaeure or salts thereof with an amine of formula II in the R deep 1, R deep 2 and R deep 3 is hydrogen or lower alkyl radicals having 1 to 3 carbon atoms, optionally denote with one or more hydroxyl groups, with CaCl 2 deep is recovered. The salification is carried out in aliphatic alcohols having 1 to 3 carbon atoms, optionally with a proportion of water which does not exceed 25% of the total volume of the solvent mixture.

Description

Title of the invention

Process for the preparation of calcium bia- (di-n-propyl acetate)

Field of application of the invention

The invention relates to a novel process for the preparation of calcium bis-Cdi-n-propyl acetate) of the formula

- CH ₁

CH - COO

- CHo - CH,

Ca

which is used in human medicine preferably in the drug therapy of epilepsy.

Characteristic of the known technical solutions

Calcium bis-cdi-n-propyl acetate) (I) has been known since 1889 [Flirth, Monatshefte der Chemie, 2 (1889), S, 320322] The preparation of I is also described in U.S. Patent 3,814,812 and mentioned in the DD-PS 129 776, page penultimate paragraph.

According to these processes, I is obtained by neutralization of an alkaline earth base with di-n-propylacetic acid with the formation of water of neutralization of water. All the above-described processes adhere to different waxes. The sparingly soluble

also extended ness νου alkaline earth metal such as CaO or Ca (OH) ₂ in the usual solvents, especially in water, unfavorable · This Sciiwerlöalichkeit not only has the consequence that one has the intended reactions usually perform at the boiling point of the solvent, but leads Reaction times and not in each case to complete conversion of the reactants · On the other hand, since I in solvents, especially in water, is sparingly soluble, prepares the preparation of pure Ceticium bis (di * npropyläcetat) (I) difficulties ·

In addition, it has become known from the recent patent literature (BE-PS 884 848) that salts of di-npropylacetic acid tend to combine with di-n-propylacetic acid in molar ratios to "dimeric" molecules, which in previously known Process for the production of ionic and purity modifiers can »

I contains the anticonvulant effective di-n-propylacetic acid and is widely used in the drug therapy of epilepsy because of its tolerability and convincing therapeutic efficacy. This has led to a high degree of commercialization which makes it imperative to have improved methods of producing I to develop·

Object of the invention

The object of the invention is to produce I in a particularly simple process and in high purity. In particular, the invention makes it possible to use I more readily available raw materials in an economical, more environmentally friendly manner

and energy-saving it can win in high yields and in high yields.

Representation of the essence of the invention

The object of the invention is to develop a novel process for the preparation of I, in that, with regard to the nature of the crude substances to be used, the reaction sequence and the achievable yields and purity of the final product show advantages over known solutions.

According to the invention the object is achieved by the fact that for the preparation of I Umaalzung an alkali salt of di-η-propylesaigaäure or aea salt thereof with an amine of the general formula

R ₁ -HE ₃

wherein R, ^, R ₂ and R- represent a hydrogen atom or a lower aliphatic Kohlenwaaseratoffrest with 1 bia C atoms, which may optionally contain one or more hydroxyl groups, with CaCIp in a lower aliphatic alcohol having 1 bia 3 C atoms optionally does not exceed a proportion of water of 25% based on daa Geaamtvolumeη dea alkoholiachen aqueous solvent is carried out at temperatures of 0 ⁰ C to the JE,

from 0 ^° C. to the boiling point of the solvent,

As alkali metal salt of di-n-propylesaigaäure is, for example, sodium üi-n-propyl acetate, which is available in a conventional manner according to descriptions in DD-PS 129 776. Ea is indefatigable after the

It is not necessary to carry out a separate preparation and isolation of such an alkali metal salt or else an amine salt of di-n-propylacetic acid proposed according to the invention. Rather, the method of the invention provides that even solutions of such salts, as they easily arise by simply dissolving alkali metal hydroxide or an amine of general formula II and di-n-propylacetic acid in atöelaionietriachen proportions in one of the present invention proposed alcoholic or aqueous-alcoholic solvents, be reacted with CaCl ₂ or a solution of CaCl ₂ in one of the solvents proposed by the invention. The order of the reaction partners can be chosen so that either alkali metal hydroxide or the amine used is dissolved in addition to dinopropylacetate and CaCl ₂ , optionally in solution , Is stirred or that one dissolves CaGl _{2 in} addition to di-n-propylesaigsäure and alkali hydroxide or a corresponding amine, optionally in alcoholic or alcoholic-aqueous solution.

In cases in which the amine used is gaseous under normal conditions, this amine can also be introduced into the solution of the other reactants, CaCl ₂ and di-n-propylacetic acid, in the amounts required for the reaction.

Suitable amines of the general formula II are, for example: methyl or ethylamine, dimethyl, diethyl, dipropylamine, trimethylamine and triethylamine, aminoethanol, mono- and dimethylaminoethanol, bis-diethanolamine

An advantageous feature of the listed amines is their property of forming readily soluble HCl salts in alcohols or aqueous alcohols having 1 to 3 carbon atoms and a maximum of 25 % water.

In the case of the use of alkali salts ν or ¹ dea ammonium salt of di-n-propylacetic acid in the erfindungagemäßen production of I, in particular when the solvent is free of water or contains low percentages of water, first salt mixtures of I and the mitentstehem each Alkalibzw * Ammonium chloride are formed since the latter have only limited solubility in such cases * -

Ea, however, succeeds in achieving the freedom of chloride from I by the subsequent treatment of a salt mixture with water, such as intensive washing out, resting, or boiling with water.

In the cases in which amines of the general formula II are used, which form easily soluble HCl salts in alcohols or water-containing alcohols, I without chloride contents is also obtained without waxing treatment with water.

The examples demonstrate the method according to the invention without restricting it.

Example embodiments Example 1

114 g (about 0.8 mol) of di-n-propyleasigsäure are dissolved in 300 ml of a mixture of 80% methanol and 20% water and 32 g of sodium hydroxide (0.8 mol) were stirred · while warming to about 40 ⁰ C A bright solution is formed quickly. »A bright filtered solution of 44 g CaCl ₂ (0.4 mol) in 400 ml of an 80% aqueous methanol is added dropwise to the blank solution within 15 minutes

Salt precipitation · lach after 15 minutes of stirring is cooled with flowing external water cooling and vacuumed after several hours of crystallization of the crystal · After good pressing is first washed twice with 10Ö ml of methanol · spell the filter residue is stirred with 400 ml of hot water and filtered off with suction · Wash with 150 ml of hot water and dried at 105 ° C «yield of I 78 g ($ 60 % of theory).

Example 2

114 g of di-n-propylacetic acid (approx. 0.8 mol) are stirred in ml of methanol, 95% of gold, and 32 g of (0.8 mol) acrylate. The bare solution is then stirred with rapid flow and filtered with a bright filter Solution of 44 g CaCl ₂ (0.4 mol) in 350 ml of methanol (95 igig), where it comes quickly to salt precipitation · is now stirred for 30 minutes with flowing water cooling and then sucks off the crystal slurry. The filter residue is washed twice with 50 ml of methanol. After drying at 105 ⁰ C obtained 137 g of a salt mixture, the wholesale addition of 20% UACL about 80% Calciumbi (di-n-pro pylac et at) (I), contains · The salt mixture for 30 minutes with 400 ml of 80 ^{Stirred 0} C hot water and filtered hot * The filter residue is washed twice with 100 ml of hot water · After drying at 105 ⁰ C remain 98 g of I (about 75% of theory). Chloride content is less than 0.01%, the content of non-ionically bound di-npropylacetic acid below 0 ^ 3rd

Example 3,

The procedure according to Example 2 is carried out with replacement of the methanol by the same volume amounts of ethanol, 96% strength, 96 g of I (Auabeute ca · 74 % of theory). r

Example 4

17.8 g of sodium are added little by little in 500 ml of n-propanol. After the reaction has ended, 114 g of di-n-propylacetic acid are stirred in, followed by 44 g of CaCl ₂ dissolved in a further 400 ml of n-propanol. Ee comes to the precipitation of a salt mixture, which is completed by further stirring overnight with flowing Waaeerkühlung »

After aspirating the Salzgemiachea and treating with 80 ⁰ C hot Waaaer according to Example 2 gives ca _e 90 g I (ft 69 % of theory) ^

Beiapiel 5

32 g (0.8 mol) of KaOH are added in 400 ml of methanol (99.5%) yellow'at and 114 g of bi-n-propyleaaiga acid added. The bare Löaung is within 15 minutes by dropwise addition with a filtered Löaung of 44 g CaCl ₂ in 400 ml of methanol. In this process, ea is gradually added to a salt salt precipitate which is readily mixable. The mixture is subsequently stirred for a further 3 hours with external fluid cooling and then filtered off with suction. The filter residue is washed twice with 100 ml of methanol each time. Bach, dried, gives 145 g of a salt mixture of I and NaCl, after boiling with 400 ml of Ytiasser, suction of the undissolved and washing

: '. - 8th. -'. ·. . ·.

this residue with 100 ml of water gives 104 g chloride-free I (80 % of theory).

Example 6

144 g of bi-n-propylacetic acid (1.0 mol) are dissolved in 500 ml of methanol, neat, 99 % pure, and 101 g of triethylamine predried over KOH are added rapidly, during which the solution heats up slightly. The solution is then stirred a blank-filtered solution of 55 g of anhydrous CaGl ₂ in 500 ml of methanol. During the addition, a pulpy precipitate is gradually formed, which is completed after 2 hours of stirring with flowing water cooling after the amine has been infiltrated. The crystal pulp is then removed by suction , presses it and well washed twice with 150 ml of methanol · wax change of template is washed with water until complete freedom chloride · Hach drying at 105 ⁰ C are obtained 131 g of pure I ($ 80% of theory) ·

Example 7

72 g of di-n-propylacetic acid (0.5 mol) and 28 g of anhydrous CaCl ₂ (0.2545 mol) are dissolved in 400 ml of methanol, pure, 99.5%, bright · In the blank solution, a solution of 45 g of dimethylaminoethanol in 300 ml of methanol, pure, 99.5% pure, added dropwise within 30 minutes. It comes with stirring to a rapid crystallization, which is completed by standing for several hours the reaction mixture at 0 ⁰ C. After vacuuming the Xristallisats, washing twice with 100 _a ml of methanol and final washing with water to obtain after drying at 105 ⁰ C about 7OgI (It about 85 % of theory).

An approximately identical result for the same course is obtained, instead of dimethylaminoethanol 37.5 g of Honomethylaminoethanol or 30.5 g of ethanolamine are used νϊβηη.

Example 8

72 g of di-n-propylacetic acid (0.5 mol) are dissolved in 250 ml of a methanolic dimethylamine solution containing 22.5 g of dimethylamine »In the solution is allowed at a bath temperature of 40 ⁰ C with stirring un4 Rückflußkühlung a solution of 28 g of anhydrous ₂ in 350 ml of methanol, pure, 99.5 $ ig _f run · After initial solution a rapidly enhancing salt precipitation occurs · After 15 minutes of stirring at boiling temperature, with a complete solution used, the clear solution up to 12 cooled ⁰ C internal temperature and left 2 hours, the crystallization · is then filtered off and washed twice with 100 ml of methanol · Uach drying remain almost 70 g of I (it 85% of theory) *

Claims (1)

- 10 claims 1 «Process for the preparation of Caleium bis (di-npropylacetat) of the formula GH-5 - CH - COO, Ca ' characterized in that an alkali metal salt of di-n-propylacetic acid or a salt thereof with an amine of the general formula E ₂
R ₁ - Έ - in which R ₁ , Rg and Ro denote hydrogen atoms or lower aliphatic Alkylreate having 1 to 3 carbon atoms, optionally with one or more hydroxyl groups, with calcium chloride in a lower aliphatic alcohol having 1 to 3 carbon atoms, optionally with a proportion of water up to 25 % of the volume of the aqueous-alcoholic solvent mixture, at temperatures of clay O ⁰ C to "at the boiling point of the solvent," Method according to item 1, characterized in that _; that a solution of stoichiometric amounts of an alkali metal hydroxide or amine of the formula II and di-n-propylacetic acid in a lower aliphatic alcohol having 1 to 3 carbon atoms, optionally aiit with a proportion of not more than 25 % based on water daa volume of the alcoholic-aqueous solvent mixture, with calcium chloride or its solutions in the solvents mentioned in point 1, reacted, 3 · Method according to item ί, characterized in that di-n-propylacetic acid and calcium chloride in a lower aliphatic alcohol having 1 to 3 carbon atoms, optionally with a maximum of 25 % water based on the volume dea alcoholic-aqueous solvent , dissolves and the solution of a stoichiometric amount of an alkali metal hydroxides or an amine of the general formula II, optionally in alcoholic or alcoholic aqueous solution, added * 4. The method according to item 1 to 3, characterized in that optionally aftertreated salt mixtures of I and alkali chloride or II hydrochloride with water to the chloride-free «