CS223270B1 - Method of making the disodium salt of the 1-hydroxyethan-1-1-diphosphone acid - Google Patents

Abstract

The invention relates to a process for the production of disodium salts of 1-hydroxyethanol 1,1-diphosphonic acid suitable for * radiodiagnostic preparation preparations. The method of production is based on that the aqueous solution of the crude acid obtained by the reaction acetic acid with phosphorus trichloride and hydrolysis of the resulting product is concentrated, the precipitated acid is recrystallized from ice acetic acid and obtained crystalline 1-hydroxyethane-1,1-diphosphonic acid monohydrate is neutralized in aqueous medium sodium hydroxide to pH 4-7; concentration or addition of solvent, s preferably the ethanol obtained from the above disodium salt.

Description

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of a 1-hydroxyethane-1,1-diphosphonic acid disodium salt suitable for the preparation of radiodiagnostic preparations. The process consists in concentrating the aqueous solution of the crude acid obtained by reacting acetic acid with phosphorous trichloride and hydrolyzing the resulting product, the precipitated acid is recrystallized from glacial acetic acid and the obtained crystalline 1-hydroxyethane-1,1-diphosphonic acid monohydrate is dissolved in aqueous the medium is neutralized with sodium hydroxide to pH 4 to 7 and by concentration or addition of a solvent, preferably ethanol, to obtain the above disodium salt.

The invention relates to a process for the preparation of the 1-hydroxyethane-1,1-diphosphonic acid disodium salt of the formula I

PO3H2

CH3-C-OH

J

PO3H2 (I), free of by-products, mainly used as radiodiagnostics. It is therefore necessary to prepare a very pure preparation for this purpose, without the by-products, especially phosphites, whose quality is guaranteed by the method of preparation and by suitable analytical control.

The prior art salt preparation process (for example according to Belgian Pat. No. 672,168) does not guarantee this, since both sodium and other salts are obtained by neutralizing aqueous solutions of the crude acid, i.e. solutions obtained by reacting acetic acid with phosphorus trichloride, by hydrolyzing it with water vapor and heating to 130-140 ° C. These solutions contain varying amounts of phosphorous acid, optionally acetic acid and hydrochloric acid. This amount depends on the overall course and performance of the reaction. The sodium salts obtained by neutralizing such solutions then contain alkali phosphites or acetates or chlorides from which they cannot be separated by crystallization or other purification operations. The salts thus obtained can then be used for most technical applications but are not suitable as radiodiagnostics.

A process for the preparation of 1-hydroxyethane-1,11-diphosphonic acid disodium salt from crude 1-hydroxyethane-1,1-diphosphonic acid produced by reacting acetic acid with phosphorous trichloride, separating the bottom layer after the reaction and hydrolyzing it with water vapor, after the hydrolysis, the solution obtained is concentrated and the precipitated crude acid is recrystallized from glacial acetic acid at least once and the crystalline 1-hydroxyethane-1,1-diphosphonic acid mionohydrate obtained is neutralized in aqueous medium with sodium hydroxide to pH 4 to 7 and concentrated or added by solvent %, preferably ethanol, the above disodium salt is obtained. The salt obtained is very pure and suitable for this purpose. As an analytical control, in addition to the titration equivalent and elemental analysis, the ¹ H-NMR spectrum was proved, where, for example, the presence of phosphonates is manifested by a proton PH signal.

In this way, it is possible to prepare the mono-, di-, tri- or tetrasodium salt of said acid, optionally by adjusting the pH either by addition of acid or sodium hydroxide, to convert one salt to another.

NMR-specimen · 1-hydroxyethane-1,1-di-phosphonic acid disodium salt produced in this way shows only a triplet (3.08 ppm ·) of the respective —CH3 group, cleaved by two equivalent phosphorus atoms, which turns into a singlet by a double resonance method (decoupling) ³¹ Pj.

It is apparent from the spectrum that the substance does not contain any other protons other than -OH and is therefore not contaminated with any other proton-containing substance with a signal in the range of 1 to 10 ppm. The interaction constant of phosphorus cleavage of the methyl group by phosphorus at 15 Hz corresponds to the structure

P /

CH3C \

P rather than

OP /

CH3C \

OP where the size of the coupling constant should not exceed 7 to 8 Hz. No phosphorus proton is present; the area was recorded at about 100 times higher sensitivity and no corresponding signal appeared there. If the substance contains traces of phosphonates, they are below the sensitivity threshold of this method, i. less than 0.5 wt. There is no acetyl or ¹ acetic acid residue in the sample.

The process for preparing 1-hydroxyethane-1 H -diphosphonic acid disodium salt is illustrated in more detail by way of example. performance:

172 ml of acetic acid was added dropwise within 15 min. 44 mL of PCl 3 and the reaction mixture cooled. For 30 min. the temperature was maintained at + 5 ± 1 ° C (reaction temperature of the mixture). Then the mixture was heated slowly to reflux, which started at +44 ° C. The temperature gradually increased to +75 ° C over 2 hours. The mixture was then heated in a 120 ± 5 ° C bath for a further 2 hours while stirring the reaction. Two layers were formed; the lower viscous layer was separated, blown with steam until the distillate was neutral and then heated in a bath to 140 ^° C (bath temperature). After concentration in vacuo, the product was recrystallized twice from glacial acetic acid.

40 g (72%) of the free acid was obtained as a crystalline monohydrate.

For G2H8O7P2. H2O (mol. Weight 224)

10.69% hmiot. C, 4.46% wt. H;

I ηΗ'ΙθΖβΠΌ *

10.26% wt. C, 4.55 wt. H. Titration equivalent:

Potentiometric titration equivalent to the stated molecular weight has been determined by potentiometric titration with sodium hydroxide and it is apparent that the acid must be neutralized up to pH 5 to 6 to prepare the disodium salt. (This determination is more or less analogous to pK values phosphoric acid.]

Upon titration to pH 8.5 the trisodium salt is formed.

Preparation of disodium salt.

11.7 g of the crystalline acid monohydrate prepared according to the previous experiment was dissolved in 40 ml of water and titrated potentiometrically with 25% NaOH until pH 5.3. The solution was filtered and diluted with ethanol. The obtained crystals were filtered off and dried in vacuo. The yield was quantitative. The disodium salt crystallizes as a tetrahydrate. For CzHeCbPzNaz. 4 HaO (mol. Weight 322)

7.46% wt. C, 4.38% wt. H;

found:

7.22% wt. C, 4.20% wt. H.

Claims (1)

Subject A process for the preparation of 1-hydroxyethane-1,1-diphosphonic acid disodium salt from crude 1-hydroxyethane-1,1-diphosphonic acid produced by reacting acetic acid with phosphoic acid, separating the backsheet after reaction and hydrolyzing it with water vapor, 3. The process according to claim 1, characterized in that after the hydrolysis, the solution obtained is concentrated and the precipitated crude acid is recrystallized from glacial acetic acid at least once and the crystalline 1-hydroxyethane-1,1-diphosphoic acid monohydrate obtained is dissolved in aq. The mixture is neutralized with sodium hydroxide to pH 4 to 7, the solution is concentrated or a solvent is added, preferably ethanol.