6-AMINO-1-HYDROXYHEXYLIDEN DIPHOSPHONIC ACID, SALTS AND A PROCESS FOR PRODUCTION THEREOF

ACIDE 6-AMINO-1-HYDROXYHEXYLIDENE- DIPHOSPHONIQUE, SES SELS ET METHODE POUR LES PREPARER

English Abstract

ABSTRACT OF THE DISCLOSURE
The invention relates to 6-amino-1-hydroxyhexyliden
diphosphonic acid, of the following formula :
<IMG>
to its salts and to a process for producting the same. This
acid is produced by reacting a mixture of phosphorous acid and
phosphorus trichloride with .epsilon.-aminocaproic acid or an amide
derived therefrom at a temperature of from 50 to 150°C. The
reaction can be carried out in the presence of an organic
solvent, preferably chlorobenzene. The salts of the acid are
produced by neutralizing it with one or two equivalents of
alkaline hydroxide, preferably sodium hydroxide. The acid
according to the invention are useful especially for pharma-
cologic purposes.

Claims

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)
<IMG> (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)
<IMG> (I)
wherein the obtained acid is neutralized with sodium hydroxide.
5. The 6-amino-1-hydroxyhexyliden diphosphonic acid
of the following formula (I)
<IMG> (I)

and the alkaline metal salts thereof.

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
1 03H2
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)
1 03H2
NH2 ~ CH2 - CH2 - C~2 CH2 2 1 (I)
P3H2
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 .
.
.
- 3 -

;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.
~ .
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.
' ' ' ' . .
, . .
- 4 -
.
; .