DD215531A1 - PROCESS FOR PREPARING THE CALCIUM SALT OF DI-N-PROPYL ACIDIC ACID - Google Patents

Abstract

A pure calcium salt of di-n-propylacetic acid can advantageously be prepared by reacting a calcium salt of the general formula m (A) by n (B) II in the A calcium bis (di-n-propyl acetate), B n-propylacetic acid and m and n indicate identical or different molar numbers, where n may be in the limits of> 0.05 m to <2 m, with lower alcohols having 1 to 3 carbon atoms, optionally in admixture with a maximum proportion 50% of dimethylformamide, treated.

Description

Title of the invention

Process for the preparation of the calcium salt of di-n-propylacetic acid;

Field of application of the invention

The invention relates to a novel process for the preparation of the calcium salt of di-n-propyleaaigaäure of the formula

- CH ₀ - CH ₉ ^{2 2}

- COO

Ca ¹ * ¹ "I

This is the case in the case of calcium deficient aeti as well as because of its content of anticonvulsively active di-η-propyl. essigaic acid is used in the treatment of epilepsy.

Characteristic of the known technical solutions

Calcium bis (di-n-propyl acetate) of the formula I has been known since 1889 (Fürth, Monatshefte für Chemie, 9 (1889), p. 320 322). ', - ^:. ';'; . ·. ; ; .-:. ;; - · ;. · '-' V '. ';;:;/.:.;

Thereafter, it is without further reference to Detailsa its preparation from CaCOo and di-η-propyl acetic accessible. "In the US-PS 3,814,812 a method for obtaining I aua CaO and di-n-propylessigaäüre in water is described · In this way the production of I is also in DD-PS 129 776 page 10, penultimate paragraph * particularly reference

'. ' ^N ''''' · '«.-' 2 ~"^; - '' ^: ^ '-' "'''· ^: ' ^: '' · ''

without taking this into account in the examples. In the context of from lUrth (s. Above) nit detected anomaly in Löaungsverhälten yon I in water, the solubility of I in water at 0 ⁰ C at the bowed and decreases with increasing temperature, there is justified doubts about the reproducibility of the after cited US-PS niitgeteilten yields of I.

Repeated investigations by this method led, in addition to a large amount of gray-colored, puffy, unspecified residue, to a maximum yield of 1 of 45%.

The gray-green discoloration of the residue indicates the formation of impurities during the several hours cooking time of the water-insoluble pi-n-propylacetic acid in the strongly alkaline-reacting alkali solution. ''. , '' \\ . X; V. ·; .. '.:, ' R. ·,. ·:, '^; , ·:. ';

These disadvantages, which also exist in a high volume capacity of the process, have an unfavorable effect on the industrial production of large quantities of the calci um metal.

Another Hachteil the known solutions lies in the external nature of a conventionally prepared calcium salt of di-n-propylessigaäure that under the described conditions as talcumähnea poorly flowable powder with a relatively high Schüttvoluirien of 8 and more milliliters per gram obtained ». ^; , , , , / '' .. ·.: ... ''^:;';'· _: ..''

The representation described in DD-PS 129 776 for the sodium salt of di-η-propyleaaigaäure (see Example 1 and Example 4 of DD-PS '' - 129 776) is complicated and leads to "transfer to an analogous preparation of the calcium salt a voluminous hardly stirrable crystal pulp whose purity and freedom from unreacted lime content is not assured, and a particular complication is the practical insolubility of the calcium salt in the organic solvents used, such as toluene.

Even in the heat of the day, it is barely soluble in common organic solvents, such as gallium bis-Cdi-n-.pro-pyi. Thus, boiling toluene dissolves less than 0.1 $ a, boiling acetone less than 1 %, and 100 ⁰ C hot dimethylformamide less than 2 % * " .

The deficiencies of previously known solutions have an effect on the technical realization of the processes for the purpose of producing large quantities _.

Object of the invention

The invention makes it possible to produce the compound of the formula I technically easily, economically and in optimum yields, wherein the resulting compound of formula I is free from residues of alkaline starting materials, shows advantageous crystallization conditions and can be obtained in an external state, which facilitates the galenic processing.

Explanation of the essence of the invention

The invention has the object to develop a new process for the preparation of calcium ^ bis-Cdi-n ^ propylaeetat) of formula I, which is technically easy to implement and provides a salt which is free from residues of alkaline starting material e ' is obtained in an economically favorable manner and in optimal / yields, which shows advantageous crystallization conditions and can thereby be obtained in an external state which facilitates galenic processing.

According to the invention this is achieved by reacting a calcium salt of di-n ~ propylacetic acid of the general formula: ./ '' ·. '. , . '; .-: ".. ""'"" · ,, ^: ;;' . ' / - '; ^λ;:;:' m _[: A] · η Γ 3] ^[; II: '/ ....

where A = calcium-bis - (di-n ~ propyl) the iOrmel I means B ftirpi-n-propylacetic is and m and η specify the same or different numbers of moles ^ wherein η within the limits of 0.05 m} ^ to 2m, with a lower alcohol with i to 3 ö-A-toinen or a solvent mixture of a lower alcohol having 1 to 3 C-atoms and Dimeihyiformamid whose proportion of the solvent mixture up to 50 ^. can be treated. . : '... ";:>;/" - [':'] :; '; ·. '. , ^: ; _,; While lower alcohols having 1 to 3 carbon atoms do not dissolve the salt of the formula I to be prepared very well and I is sparingly soluble in hot dimethylformamide, solvent mixtures of alcohols and dimethylformamide are present in an amount of up to 50 %. Dimethylformamide Löalichkeit an unexpected rise in the temperature increases, so that this solution middle! Mixtures in which it £ limited indungsgemäß

Composition not only allow the conversion of a calcium salt of the general formula II in the Caiciumsalz of Formel.I, but at the same time exert a purifying recrystallization effect · The available crystals are well formed and show optimal debris volumes between 2.5 and 3.5 ml per grams. '. , '. ··; .. '"· ... / ^; / ^: "''.'\' - '-'''.

A further particular embodiment of the invention provides that a solution of a salt of the general formula II.in organic solvents such as toluene, benzene, acetone, lissigsäureäthylester and others are used and these with the inventively proposed solvents or solvent mixtures at room temperature or elevated temperature up to Boiling temperature of the solvent mixtures treated.

After another. Embodiment of the invention 'it is also possible, as solutions of the salts of the general formula II, the reaction products of calcium oxide, calcium hydroxide or calcium carbonate and di-n-propylacetic acid in for the preparation according to the simultaneously filed GDR patent application WP C 07 D / ,. . or to use according to the Belgian Pat. No. 884 848 used organic solvents, without any special isolation of salts of the general formula II is made. Z we cianäß ig is filtered one by the "method of the .zitierten East German patent application and the cited Belgian patent corresponds ^obtained: speaking Reaktionsmiachung of: possibly undissolved constituents and then, but may not be necessary, treating them under partial or complete distillation of Solvents, according to the invention at room temperature or at elevated .Temperatur with lower alcohols having 1 to 3 carbon atoms or a Lösungs- j

medium mixture of one, lower alcohol with 1 to 3 CA atoms and e in em; up to 50% of dimethylformamide, '. '' r - ^: - ' . '";': ':. .- · '·'. ''^':.;'

The process of the invention can be carried out at temperatures between room temperature and the boiling point y of the reaction mixture.

Purly the erfindungagemäße method can be used arbitrarily composite salts of general formula II. The higher the proportion of non-ionic bound di-n-propylacetic acid, the easier is the solubility in the solvents or solvent mixtures used in the invention, which even at room temperature rapid solution takes place, which after a short time to precipitate the Caleiumsalzes the formula. I leads. ".."...; .. ..; ^; ; , '. ".

In the interest of a slower Auskristallisätion you can make the Lösuhgsvorgang in the invention used according to the solvents or solvent mixtures but also with heating to the boiling point of the solvent or Lösungsmittelgemisehe and crystallization, optionally after crystallization, by a gradual cooling to .. weitschreit crystallization of the salt of formula I perform.

In cases where a one-time treatment of a salt of general formula II by dissolving a salt of formula II in inventively proposed Lcaungsmitteln or solvent mixtures at room temperature or at elevated temperatures up to the boiling point of the solvent or Lösungsmittelgemisehe to a salt of formula I with still present Rest-

should lead to shares of non-ionically bound di-n-propylacetic acid, which may account for example, 3 % of free di-n-propylacetic acid based on the total mass of the salt, the procedure according to the invention may be repeated and thereby a complete separation of the non-ionically bound di-n-butyl be achieved propylacetic acid, '. _.-..-. : '': '': '.': ''. · Ν '. · ^: .;: ' _: .-.

However, this is not absolutely necessary for clinical use and for galenic purposes. Rather, it is also possible, a obtained according to the invention calcium salt of Üi-n-propylacetic acid, which still contains small residual amounts of non-ionically bound di-n-propylacetic acid, z, B, 0.1 to 3.0 % _t directly for galenic processing to use.

The advantage of the process according to the invention is that the starting salts used in the process; 3? Oriael Il; ';;'. show good solution properties in the Lösungsmittein applied in the solvent or solvent mixtures, wherein at the same time in contact with the alcoholic solvents used in the invention, optionally; with maximum proportions of 50 % dimethylformamide, based on the amount of solvent mixture, decomposition of the salt of general formula II used according to the invention into the calcium salt of di-n-propylacetic acid of formula I and into free dissolved di-n-propylacetic acid. From the solutions, a well-crystalline, neutral-reacting salt of the formula I in purified form is obtained in high yield with cooling, in high yield.

The effect of the conversion of salts of the formula II into the salt of the formula T achieved by the process according to the invention is surprising and unexpected insofar as

identical treatment of salts of the general formula II KiIt other common organic solvents ale.den inventively proposed such as toluene, benzene, esters and ketones, given älis even in the presence of water, does not lead to the same effect as the inventively proposed treatment with lower Alcohols, optionally in the presence of limited amounts of dimethylformamide. ,:; '.-. · Y''' ^y - :: '', - '. :

Rather, can check noted that in some cases even opposite effects using other than the erfindungsgenäß proposed solvent or Lösungsmittelge -, misehe can be connected to it · Thus, an Umkristal-Ii sa tion of a salt of the general formula II .with a content of ca _# 30% of not bound di-n-propylacetic acid in toluene not only in the absence of "Bi ~ n-propylacetic acid, but in a slight increase in the content of non-ionically bound di-n-propylacetic acid in the acid-crystallizing salt"

This phenomenon may be described as a disproportionation of the acid salt of the general formula II into a large proportion of a salt of the general formula II, which proceeds in relatively narrow limits in the solvent toluene

 , · '' \ -. ·. , , "with a slightly higher proportion of non-ionically bound di-n-tpropylessigsäure and in a small proportion of a salt of the general formula II lower er content of non-ionically bound di-n-propylessigsaure" Ss is a feature of the invention that the invention For the treatment of salts of the general formula II, alcoholic solvents or alcoholic solvent mixtures are reacted in the same way as other organic solvents and as a crystallizing home product give a salt which corresponds to the calcium salt of the formula. V.

After separation of the crystallized main product, there is such a large degree of distilling off of the solvents or solvents used according to the invention, in addition to di-η-propyl-acetic acid, a slight residue which shows increased values of non-ionic bonded di-n-propylacetic acid. γ., - _: ,; ; \ '. : '/.,'. ; ' , . ·. .. ·: '·;: ^-:': '* .- ^..'..

The compounds of the general formula II used as starting materials, whose preparation is not the subject of the present invention, can be obtained, for example, according to the simultaneously filed German patent application WP C 07 D / or also according to Belgian patent 884 848, in that n-propylacetic acid in an amount greater than that required for the oil neutralization with an alkaline earth oxide, hydroxide or carbonate ·

The following examples illustrate the process of the invention. '.' , , .-. ';. · '. '·.'. ·; /. '-: \:''']'/' ^: ':'':"['',

AuafUhrungabeiapiele ^

example 1

100 g of a calcium salt of di-n-propylacetic acid containing 18 % of nonionic-bonded di-n-propylacetic acid are dissolved at room temperature in 500 ml of methanol. Hach fast dissolution process is a momentary Auafällung a thick Salzbreiea. It is suctioned off, wäecht with methanol and the Salzbei 110 ⁰ G. dried to give 77.5 g of a Calciumaalzes, containing a residue (1.9%) of non-ionic bound di-n-propylacetic acid. laughing again cooking of the salt in 400 ml Methanoi, cooling, suction remain after JProcknung at 100 ⁰ C 75 g of a Calciumaalzes whose content is not ionic gebundiener Di-n-propylessigaäure below 0.5% ·

; '': - 1Q- VV-- WV _; V: ·. :

Example-2. '':>'v'V /. ^:; - ''''. /

a) 40 g of di-n-propylacetic acid and 5.5 g of GaO are heated in 75 ml of toluene with stirring and Rüekflußkühiung ' boil for 15 minutes. Ea is filtered hot, leaving no weighable residue. The bright solution is treated according to b) »

b) The pure toluolisehe solution according to a) is added with heating to about 80 ⁰ C with 125 ml of ethanol and then left without further heating a slow cooling, after several hours of crystallization is filtered off with suction and washed the FiIterrücketand with 50 ml of ethanol. The calcium salt of dinopropyl acetic acid with a residual content of di-n-propyl33-enoic acid below 0.5 % is obtained. in an amount of 28 g (87.5 % of theory based on CaO) _f ;

a) In a 2-liter Drelhal® flask with stirrer and reflux condenser, 700 ml of aqueous, about 85 / iger acetone ^{x are} introduced and 127 g of di-n-propylacetic acid (0.88 .Mol) was added. 22.0 göaö (97.5%, ca "0.39 mol) are stirred quickly into the blank solution, with warming up to 42 ⁰ C occurs, .The slightly milky cloudy suspension dissolves almost completely within a few minutes to a slight opalescent solution. To complete the reaction, heat on the steam bath aa3 mixture and keep it for 15 minutes in a slight boil. It is then filtered hot over a glass frit G 4, wherein eänkaum be weighed Prittenrückstand obtained.

The bare solution is cooled to 15 ⁰ C and after 3 hours a colorless crystals are filtered off with suction. you

Wash the Rücketand twice with 75iDl Seigern aqueous acetone After drying at 50 ⁰ C to obtain 100 g of a salt with 10.4 % non-ionically bound di-n-propyl acetic acid (yield 87% of theory), ^

b) 10 g of the calcium salt of di-n-propylacetic acid prepared according to a) are in'50 al. Solvent of the parent compound of 90 % methanol and 10 % dimethylformamide is dissolved with heating under blank, while being gradually cooled, it is subjected to cryolitization. Well-formed large crystals of calcium di-n-propyl acetate, which after washing with methanol and drying in a yield of 90 '% .... the theory accrue The resulting calcium di-npropylacetat is free of non-ionic Di-n-propylacetic acid · -; / · · · ·

Example 4. '. ''::; ^: -'''':''''''' : ^; - ^; V An analogous result is obtained when the procedure is as in Example 3, but instead of ethanol n-prppanol begins, ^: \

Claims (4)

;. · ·; ..., - ig - -::. ; : y: - y'-. / Claims Λ. '...;' '. ^: '. ..: 1. A process for preparing the Galciumsalzes of di-n-propyl acetic acid of the formula GH ₃ - CHg - GH ₂ GH, OQD ¹ . Ca characterized in that one comprises a Galciumaalz of di-n-propylacetic acid / the general formula in which A Ga3cium-bis ^(di-n-i pröpylacetat ') of the formula I is, for ateht B Di-n-propyleasigsäure and m and η specify identical or different liolzahlen, · wherein η within the limits of _)> 0 , 05 m to <"2 m, with a lower alcohol having 1 to 3 carbon atoms or with a Xosungsmittelgemiach of: a lower alcohol having 1 to 3 carbon atoms and dimethylformamide, the proportion of the solvent mixture bia to 50 fi can be treated. 2. The method according to item 1y, characterized in that one uses solutions of the salts of the general formula II in organic solvents v / ie .Benzol, ^^ toluene, acetic acid esters or ketones such as acetone or Methyläthylketön «,; '; '.' 3. Process according to the points T and 2, characterized in that one in the preparation of the compounds of general formula II in organic; Solvents such as benzene, toluene, acetic acid ester or ketones, such as acetone or methylethylketone, if appropriate after partial or complete removal of the alcohol B. , - '. ':'['.'-" ^: , r--'. '/ ^: ' // _: '.' _: "-. _: ·; ' , '.'- 4 · Method according to items 1V to 3, characterized in that at room temperature or elevated temperature up to the boiling point of the solvent or of the solvent mixtures ·