PROCEDE D'OBTENTION DE SELS DE L'ACIDE (-) CIS-1,2-EPOXYPROPYLPHOSPHONIQUE

METHOD FOR PREPARING SALTS OF (-)CIS-1,2- EPOXYPROPYLPHOSPHONIC ACID

Abrégé anglais

Abstract of the Disclosure
This invention relates to a novel process for preparing
(-)cis-1,2-epoxypropyl phosphoric acid and salts thereof with
non-toxic bases. The process comprises oxidising cis-l-propenyl
phosphoric acid to produce the corresponding racemic epoxy acid,
adding L(+)-threo-l-(p-methylmercaptophenyl)-2-amino-1,3-
propanediol as a resolving agent, alkalinising the suspension
and isolating the acid salt with the base. These products are
useful to inhibit the growth of both gram-positive and gram-
negative pathogenic bacteria and are used in both the human and
veterinary fields. The process, using thiomicamine as the resolv-
ing agent, is a more efficient process than the prior art and
allows for almost a complete recovery of the resolving agent.

Revendications

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A process for the preparation of (-)cis-1,2-
epoxypropylphosphonic acid salts with non-toxic bases which
comprises:
(a) oxidizing cis-l-propenylphosphenic acid to produce
the corresponding racemic epoxy acid;
(b) adding L(+)-threo-l-(p-methylmercaptophenyl)-
2-amino-1,3-propanediol as a resolving agent;
(c) alkalinising the thus obtained suspension of the
salt of (-)cis-1,2-epoxypropylphosphonic acid;
(d) isolating the (-)cis-1,2-epoxypropyl phosphonic
acid salt with the base.
2. A process as claimed in claim 1 wherein the
oxidising of the cis-l-propenylphosphonic acid is conducted with
hydrogen peroxide in the presence of sodium tungstate dihydrate.
3. A process as claimed in claim 2 wherein the
resolving agent is added after complete decomposition of the
sodium peroxide.
4. A process as claimed in claim 1 wherein the sus-
pension is alkalinised with sodium hydroxide.
5. A process as claimed in claim 3 wherein the sodium
peroxide is completely decomposed by treating the solution with
hydrazine hydrate and a catalytic amount of reduced copper at a
temperature from about 45°C. to about 50°C.
6. A process as claimed in claim 1 wherein the pH
of the mixture is maintained at about 5 to about 6 during the
addition of the resolving agent.

Description

~L3~6~1~
1 ~his inven-tion relates yenerally to antibio-tic pre-
parations, and more particularly, to a new process for the
preparation of salts oE (-)cis-1,2-epoxypropylphosphonic acid.
In the past, various methods have been proposed to
produce (-)cis-1,2-epoxypropylphosphonic acid and the salts
thereof. The acid and its salts, alone or in combination with
non-koxic bases, are widely used in both the human and ve-terinary
fields to inhibit the growth of both gram-positive and gram-
negative pathogenic bacteria.
The process for the preparation of the racemic epoxy
acid of the formula (I)
CH3 - CH - OEl _ p \OH (I)
O OH
is well known. It is also known to resolve the racemic epoxy
acid into its optically active isomers. One of the most widely
I used resolving agents is (-~)-alpha-phenethylamine.
This process of the prior art has drawbacks in its
efficiency and diffiaulty in obtaining good yields. Accordingly,
it is an objec~of the present invention to at least partially
~ overcome these disadvantages by providing a novel process for
the preparation of (-)cis-1,2-epoxypropylphosphoni~ acid salts
with non-toxic bases.
To this end, in one of its aspects, the invention
provides a process for the preparation of (-)cis-1,2-epoxypropyl-
phosphonic acid salts with non-toxi¢ ~ases which comprises:
(a) oxidising cis-l-propenylphosphenic acid to produce
the corresponding racemic epoxy acid;
(b) adding L(+)-threo-l-(p-methylmercaptophenyl)-
2-amino-1,3-propanediol as a resolving agent;
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(c) alkalinisiny the thus ob-tained suspension of the
sal-t of (-)cis-1,2-epoxypropylphosphonic acidi
(d) isolating the (-)cis-1,2-epoxypropyl phosphonic
acid salt with the base.
The present invention provides a method for prepariny
salts of (-)cis-1,2-epoxypropylphosphonic acid of the formula (I)
OH
C~3 - CH - CH - P ~ (I)
\O/ OH
with non-toxi¢ bases, by using cis-l-propenylphosphonic acid
of the formula II /OH
CH3 - CH = C~ - P ~ (II)
O
-~ as the starting material and L(~ threo-l-(p-methylmercapto--
~ phenyl)-2-amino-1,3-propanediol (hereinafter referred to as
thiomicamine) as the resolving agent for the racemic epoxy acid
! of the formula (I). The recovery rate of the thiomicamine
used in this invention has surprisingly been found to exceed 93%.
The process of this invention comprises first oxidising
the cis-l-propenylphosphonic acid of the formula II with hydrogen ~.
peroxide in the presence of sodium tungstate dihydrate to form
the racemic epoxy acid of the formula I. Thiomicamine is then
added after the hydrogen peroxide has been completely decomposed
to prevent its oxidati~n.
The thus obtained suspension is then alkalinised with
sodium hydroxide to yield a solution of the sodium salt of
(-)cis-1,2-epoxypropylphosphonic acid which is then converted
: into a salt of the desired base by a suitable treatment.
;~ It ls necessary to completely decompose the hydrogen
peroxide before adding the thiomicamine. A preferred method of
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1 decomposing the hydrogen peroxide quic~ly is, after the oxidation
reaction has been comple-ted, -the reaction solution is treated
with hydrazine hydra-te and a catalytic amount of reduced copper,
a-t a temperature from about 45C. to about 50C.
Thiomicamine is added gradually to the reaction solu-tion
which contains the racemic epoxy acid of the formula I. The
pll is kept at about 5 to about 6 by suitable acidification during
this addition step.
The following examples are given by way of illus~ration
only of the process and are not limiting in nature. Although
the disclosure describes and illustrates a preferred embodiment
of the invention, it is to be understood the invention is not
restricted to this particular embodiment.
Example 1
. . _, .
Preparation of the calcium salt of (-)cis-1/2-epoxy-
propylphosphonic acid monohydrate.
600 g (4.91 mols) of cis-l-propenylphosphonic acid
were dissolved into 3,S00 ml of water and the thus obtained
solution was adjusted to pH S~9 with 30% sodium hydroxide.
solution containing 11.2 g sodium tungstate dih~drAte, 4.8 g
edetate disodium and 53 ml water was added ko the above prepared
solution under stirring and working at room temperature.
The solution thus obtained was heated to 45 - 50C
and 620 g (7.3 mo~s) 40~ hydrogen peroxide was added slowly
under stirring. After the addition was completed, the solution
was allowed to stand under these conditions for one hour and a
~al~.
3.2 g (0.064 mols) hydrazine hydrate and 0.32 g reduced
copper was poured then inko the solution.
The solution free of the oxidiæing agent was cooled
-- 3 ~

`
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1 to 20C, decoloured, filtered off and treated with 1,045 g (4.91
mols) L(~ threo-l-(p-me-thylmercaptophenyl)-2-amino-1,3-propane-
diol (Thiomicamine) and concentrated hydrogen chloride by working
at room temperature and under stirring.
Thiomicamine was gradually added and alternated with
the addition of hydrogen chloride in order to keep the pH of the
mixture between 5 and 6 The p~ was 5.8 at the end of the
addition.
The mixture was kept one hour under stirring at room
temperature, then cooled to 0C. and, after two hours, the
precipitate was filtered off and washed with water. From t he
mother liquor, 265 g Thiomicamine was recovered by alklinization.
The precipitate obtained as described above and consisting of
the Thiomicamine salt of ~-)cis-1,2-epoxypropylphosphonic acid
was crystallized from isopropyl alcohol and suspended in 2,~00
ml water. The mixture was stirred at room temperature and
alkalinized with 10% sodium hydroxide.
After one hour under stirring, the still present
Thiomicamine was filtered off. The dried Thiomicamine weights
570 g.
The calcium salt of (-)cis-1,2-epoxypropylphosphonic
acid monohydrate was precipitated from the aqueous solution
containing the sddium salt of (-)cis-1,2-epoxypropylphosphonic
acid by treatment with a 76Q g (3.~7 mols) solution of calcium
` chloride hexahydrate in 760 ml water, and then filtered off,
washed with water and dried. 250 g. of produ~t was obtained.
]D = -6 (0-3% H2O) ; l~ = -18 (0.3~ H O)
By distilling off the isopropylalcohol present in the
isopropanol mother liquor obtained by crystallizing the

1~3~6~
1 Thiomicamine s~lt of (-)cis-1,2-epoxypropylphosphonic acid,
141 g Thiomicamine was recovered by alkalinization.
Example 2
Preparation of the calcium salt of the (+) cis-
1,2-epo~ypropylphosphonic acid monohydrate.
By conducting the process as described in Example 1,
and substituting the L~+)-threo-l-(p-methylmercaptophenyl)-2-
amino-1,3-propanediol for D ~-) -threo-l-(p-methylmercaptophenyl)-
1 2-amino-1,3-propanediol, 245 g of (+)cis-1,2-epoxypropyl calcium
phosphonate monohydrate we~e o~tained.
~ 6 (0~3% H20); ~J = + 18 (0-3% H20)
Example 3
Preparation of disodium salt of (-)cis-1,2-epoxy-
propylphosphonic acid.
The process of example 1 was repeated until the aqueous
solution containing the sodium salt of (-)cis-1,2-epoxypropyl-
phosphonic acid was obtained.
The pH of the solution was adjusted to 8.8 by the
addition of acetic acid, and the solution was then evaporated
under vacuum thus obtaining a syrup. The disodium salt of (-3cis-
1,2-epoxypropylphosphonic acid w~s obtained from the syrup after
treatment with ethyl ~lcohol.
Yield - 285 g.
r~ = -5 (5% H2O); ~ = -17 (5% H2O)-
., .