CA1146968A - 6-amino-1-hydroxyhexyliden diphosphonic acid, salts and a process for production thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The invention relates to 6-amino-1-hydroxyhexyliden diphosphonic acid, of the following formula :

Description

The present invention relates to 6-amino-1-hydroxyhexy-liden diphosphonic acid, to the salts thereof and to a process for productlng the same.
Numerous non-substituted acids of the general formula R-C-OH

P3~2 where R represents alkyl or aryl, are described in the literature.
In addition to compounds with linear ahain where R is methyl to heptadecyl, there are also described compounds with branched chain. Ethylidenhydroxy diphosphonic acid is the most known representative of these compounds.
There is at disposal a plurality of methods for their production~ the common feature of which is that the aliphatic acid or its proper derivative is subjected to the reaction with phosphorous acid or with its precursor. It is thus possible ; to let the acylating agent (chIoride oranhy~ride) to react with phosphorous acid or to heat a mixture of aliphatic acid and P2O5 with phosphorous acid, and optionally to let the corre-sponding acid to react with PC13 in proper molar ratio.
Preparation of substituted alkylidenhydroxy diphos-phonic acids is however more difficult~because substituted aliphatic acids are often sub~ected to other reactions under similar reaction conditions. An attempt to prepare some amino-derivatives from ethylenediamino tetraacetic acid was thus unsuccessfull as splitting of carboxyl and its substitution took place. There is furthermore some amino acids that are difficult also to isolate as it is impossible to use distillation for separating the reaction mixture, the starting compound, its reaction products and their esters being not volatile.
Recently it was nevertheless described several lower ~' .~ .

aminohydroxyalkyliden diphosphonic acids and their N-alkyl derivatives with at most C4 chain. These acids have extremely little basic an!ino group and give neutral salts with two equivalents of sodium hydroxide due to the vicinity of both phosphonic groups. Neutral salt is thus characterized by a high content of sodium or other metal, which can hamper its use for pharmacologic purposes.
In accordance with the present invention, there is now proposed a new acid, namely 6-amino-1-hydroxyhexyliden diphos-phonic acid of the following formula (I) NH2 ~ CH2 - CH2 - C~2 CH2 2 1 (I) and alkaline metal salts thereof, which overcomes the above mentioned disadvantages.
The invention also proposes a process for preparing this acid, which process consists in reacting a mixture of phosphorous acid and phosphorus trichloride with the ~-amino~
caproic acid or the amide derived therefrom at a temperature of from 50 to 150C. The reaction can be carried out in the presence of an organic solvent, preferably chlorobenzene.
The salts of the acid according to the invention is produced in such a way the acid is neutralized with one or two equivalents of an alkaline metal hydroxide, preferahly sodium hydroxide.
The new phosphonic acid according to the invention has other character and basicity of amino group in relation to its distance from acid groups. It forms neutral mono~sodium ; and alkaline di-sodium salt.
In the process of preparation according to the invention, the r-aminOCaprOiC acid is transformed in to the acid I under the effect of phosphorous acid and phosphorus ~ ~ 2 -~ ~ 46a3~8 trichloride in the presence or without an organic solvent.
The salts of the acid I are prepared by neutralization with hydroxide mono- or di-sodium. Instead of the -aminocaproic acid, use can be made of its cyclic or linear amide (capro-lactam, polyamide)~ which amide is hydrolyzed during the reaction.
In accordance with a preferred embodiment of the - invention, the process is carried out by heating a mixture of the E-aminocaproic acid, phosphorous acid and an aprotic solvent at a temperature 100C and adding phosphorus trichlo-ride dropwise to the mixture under stirring. Instead of phos-phorous acid, use can~ be made of phosphorus trichloride and ; of an adequate amount of water from which phosphorous acid ~ originates d1rectly in the reaction mixture. This alternative - is less advantageous because large amount oE hydrogen chloride are liherated.
Hydrocarbons or halogenated hydrocarbons, preferably chloroben2ene, are suitable as a solvent~ The reaction mixture is heated after mixing of all -the components two or three hours to 100C and the separated solid product is recrys-tallized from hot water. Further fraction can be obtained from the mother liquors by adding methanol. The pure acid dissolves in water with difficulty; its di-sodium salt is prepared by dissolving the acid in approximately equivalent amount of sodium hydroxide and by followed titration or by adding exactly two equivalents of hydroxide to a suspension of pure acid in water. The mono-sodium sa:Lt is prepared either by adding equivalent of sodium hydroxide to a suspension of the acid in water or by neutralization of this suspension with hydroxide to pH=7.
The invention will be better understood with reference to the non-restrictive examples .
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;8 Example 1 A mixture of 13 g ~-aminocaproic acid and 12.7 9 phosphorous acid in 100 ml chlorobenzene was heated under stirring to 100C and 14 ml of phosphorus trichloride was added dropwise to it within 30 minutes. The solution was than heated under stirring further 3 hours; insoluble solid matter separated during this time. The solvent was poured off after cooling, the residue was boiled with 60 ml water for about 30 minutes and subjected to hot filtration with activated charcoal through a layer of supercel. Activated charcoal and surpercel were washed with hot water and united colatures were concentrated at 40C in vacuum. Separated crystals were filtered off and further fraction was obtained from mother liquors by adding methanol in excess. Altogether 15 g (55 ~) of the crystalline acid I was obtained (melting point 245C) having i~ the IR spectrum absorption at 3.15, 6.15 and 6.45~. C6H17NO7P2 (277.2) Calculated : 26.00 ~ C, 6~18 % H, 5.05 ~ N

~, .
Found : 26.28 % C, 6.45 % H, 4~7 ~ N.
~ E~
Preparation of mono-sodium salt :

2.77 g of the acid was dissolved in 50 ml water by the addition of 10 ml 1 N Na~H, the solution was filtered and concentrated. Separated salt was filtered off, washed with methanol and dried in vacuum.
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Preparation of di-sodium salt:

2.77 g of the acid wasneutralized with 20 ml 1 N

NaOH as in example 2 and the solution was drawn off. Separated salt was dried in vacuum.

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Claims (5)

The embodiments of the invention in which an exclusive property or privelege is claimed are defined as follows:

1. A process for the production of 6-amino-1-hydroxy-hexyliden diphoshonic acid of the following formula (I) (I) and the alkaline metal salts thereof, comprising reacting -amino-caproic acid or the amine derived therefrom with a mixture of phosphorous acid and phosphorus trichloride at a temperature of from 50 to 150°C and, if desired, neutralizing the so obtained acid with one or two equivalents of alkaline metal hydroxide to obtain an alkaline metal salt thereof.

2. A process according to claim 1, wherein the reaction is carried out in the presence of an organic solvent.

3. A process according to claim 2, wherein the solvent is chlorobenzene.

4. A process according to claim 1, for the prepara-tion of a sodium salt of 6-amino-1-hydroxyhexyliden diphosphonic acid of formula (I) (I) wherein the obtained acid is neutralized with sodium hydroxide.

5. The 6-amino-1-hydroxyhexyliden diphosphonic acid of the following formula (I) (I) and the alkaline metal salts thereof.