PROCEDE DE PURIFICATION D'UN INTERMEDIAIRE DANS LA PREPARATION DE L'IOPAMIDOL

PROCESS FOR THE PURIFICATION OF AN INTERMEDIATE IN THE PREPARATION OF IOPAMIDOL

Abrégé français

Nouveau procédé de synthèse de (S)-N,N'-bis[(2-hydroxy-1(hydroxyméthyl)éthyl]-5-[(2-hydroxy-1-oxopropyl]amino]-2,4,6-triiodo-1,3-benzendicarboxamide, de la formule (III), à partir du dichlorure d'acide 5-amino-2,4,6-triiodo-1,3-benzendicarboxylique, caractérisé par une nouvelle étape de purification par chromatographie à travers des résines de dichlorure d'acide (S)-5-[[2-(acétyloxy)-1-oxopropyl]amino]-2,4,6-triiodo-1,3-benzendicarboxylique, qui permet la conversion directe vers le composé de formule (III) sans isolation préventive.

Abrégé anglais

This invention refers to a new process for the synthesis of
(S)-N,N'-bis[(2-hydroxy-1-(hydroxy-methyl)ethyl]-5-[(2-hydroxy-1-
oxopropyl]amino]-2,4,6-triiodo-1,3-benzendicarboxamide, of formula (III),
starting from 5-amino-2,4,6-triiodo-1,3-benzendicarboxylic acid
dichloride characterized by a new step of chromatographic purification through
resins of
(S)-5-[[2-(acetyloxy)-1-oxopropyl]amino]-2,4,6-triiodo-1,3-benzendicarboxylic
acid dichloride, which enables the direct conversion to the compound of
formula (III), without preventive
isolation.

Revendications

16
CLAIMS
1. Process for the preparation of (S)-N,N'-bis[(2-
hydroxy-2-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxo-
propyl]amino]-2,4,6-triiodo-1,3-benzendicarboxamide
according to Scheme 1, comprising the following steps:
Scheme 1
<IMG>
a) reaction of the compound of formula (I), 5-amino-
2,4,6-triiodo-1,3-benzendicarboxylic acid dichlo-
ride with S-(-)-[2-(acetyloxy)]propionic chloride
in dimethylacetamide in order to give a solution of
the compound of formula (II), (S)-5-[[2-
(acetyloxy)-1-oxopropyl]amino]-2,4,6-triiodo-1,3-

17
benzendicarboxylic acid dichloride in dimethyl-
acetamide;
b) elution of the resulting solution of step a) from
porous and/or macroporous cross-linked resins,
anionic and cationic, anionic resins as free base
form, cationic resins as sodium salt form, with the
proviso that the system constituted by said
solution and resin contains a water amount which
can hydrolyze the excess of S-(-)-[2-
(acetyloxy))propionic acid chloride, but which does
not hydrolyze the dichloride of compound (II};
c) possible water elimination from the resulting
solution of step b) up to a content of 0-2%;
d) reaction with serinol at a temperature of 0-10°C
for 5-20 h;
e) isolation of the compound of formula (III).
2. Process according to claim 2, in which in the step
a) the polymer structure of porous and/or macroporous
cross-linked resins is selected from the group
constituted by: acrylic-divinylbenzene, styrenic-
divinylbenzene, or metaacrylic-divinylbenzene.
3. Process according to claims 2-2, in which said
resins are arranged single or connected in series, or in
mixed bed or in floating bed and the elution is carried
out under low or high pressure.
4. Process according to claim 3, in which said resin
is a weak anionic resin arranged in a separate bed.
5. Process according to claim 4, in which said resins
are a weak anionic resin arranged in a separate bed,
followed by one strong anionic resin arranged in
separate bed.

18
6. Process according to claim 4, in which said resins
are one weak anionic resin arranged in a separate bed,
followed by a different weak anionic resin arranged in
a separate bed.
7. Process according to claim 3, in which said resins
are a weak anionic resin and a strong anionic resin
arranged in a mixed bed.
8. Process according to claim 3, in which said resins
are a strong anionic resin arranged in a floating bed
and the solution is loaded from the column bottom.
9. Process according to claim 3, in which said resins
are a weak anionic resin arranged in a floating bed and
the solution is loaded from the column bottom.
10. Process according to claim 4, in which said resins
are a weak anionic resin, followed by a strong anionic
resin, followed by a cationic resin, said resins are
arranged in a separate bed.
11. Process according to claim 1, in which the water
amount necessary for the hydrolysis of (S)-(-)-[2-
(acetyloxy)]propionic acid chloride is obtained through
water addition before elution.
12. Process according to claim 1, in which water
elimination in step c) is carried out through under-
vacuum distillation.
13. Process according to claim 1, in which
dimethylacetamide, used as solvent, is purified from
organic and inorganic salts comprising elution through
porous or macroporous cross-linked resins, anionic or
cationic resins, the anionic resins in free base form,
the cationic resins in sodium salt form.

Description

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PROCESS FOR THE PURIFICATION OF AN INTERMEDIATE IN THE PREPARATION OF
IOPA M1DOL
This invention refers to a new process for the
synthesis of (S)-N, N'-bis[(2-hydroxy-1-(hydroxy-
methyl)ethyl]-5-[(2-hydroxy-1-oxopropyl]amino]-2,4,6-
triiodo-1,3-benzendicarboxamide, of formula (III),
starting from 5-amino-2,4,6-triiodo-1,3-benzendi-
carboxylic acid dichloride of formula (I) according to
Scheme 1, characterized by a new step of chromatographic
purification through resins of intermediate (II), (S)-5-
[C2-(acetyloxy)-1-oxoprapyl]amino]-2,4,6-triiodo-1,3-
benzendicarboxylic acid dichloride, which enables the
direct conversion to the compound of formula (III),
without preventive isolation.
The compound of formula (III), (S)-N, N'-bis[(2-
hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxo-
propyl]amino]-2,4,6-triiodo-1,3-benzendicarboxamide,
better known as Iopamidol is one of the products most
widely sold ail over the world in the field of X-ray
contrast media and its synthesis is described in GB
1472050.
25
CONFIRMATION COPY

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Scheme 1
2
O C1
O C1 Me O
~CI I I
I I OAc O
Me~ ~ ~ O
w ( O Dimethyl-
H2N acetamide HN
I C1 OAc I C1
3-5°C
(I) (II)
OH OH
O N
H2N ~ OH ~H
1 5 OH O I ~ I (III)
Me ~ ~ O
Dimethylacetamide ~ HN
O-ZO°C OH I HEN OH
OH
This synthesis foresees the steps already described
in Scheme 2, including, in addition, the isolation of
intermediate (II) whose purification is necessary for
the following reasons:
- the presence of hydrochloric acid as by-product of
the reaction which can react in the successive step
with 2-amino-1,3-propandiol (serinol};
- the presence of the excess of (S)-(-)-[2-
(acetyloxy)jpropionic acid chloride which can react '
with serinol, too;
- elimination of acid by-products derivatives of
amino-2,4,6-triiodobenzoic acid.

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3
An alternative preparation of the intermediate of
formula (II) has been recently described in patent
application GB 2271990. This patent application
overcomes the problem related to a synthetic method
which excludes the use of dimethylacetamide (DMA) as
solvent by using, in the first step of Scheme 1, a
Lewis' acid in catalytic amounts in organic solvents
different from dimethylacetamide, in particular,
methylene chloride, toluene, 1,2-dichlorethane. Also in
this case, the isolation of the compound of formula (II)
is needed, which then, as cited by the authors,
continues with the procedure described in patent GB
1472050, and illustrated here by Scheme 1, which
requires another dissolution in dimethylacetamide in
order to react with serinol to give the compound of
formula (III).
On the contrary, in the process of this invention,
dimethylacetamide is kept, being this one solvent of the
successive step and in this way its elimination is
unnecessary, thus sparing a synthetic step.
Therefore this invention refers to the process for
the preparation of (S)-N,N'-bis[(2-hydroxy-1-
(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl]amino]-
2,4,6-triiodo-1,3-benzendicarboxamide of formula {III),
in a single step according to the above mentioned Scheme
1, comprising the following steps:
a) reaction of the compound of formula (I), 5-amino-
2,4,6-triiodo-2,3-benzendicarboxylic acid dichlo-
ride with S-(-)-[2-{acetyloxy)]propionic acid
dichloride in dimethylacetamide, to give a raw
solution of the compound of formula (II), (S)-5-

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[[2-(acetyloxy)-2-oxopropyl]amino]-2,4,6-triiodo-
1,3-benzendicarboxylic acid dichloride, which is
purified through elution from porous and/or
macroporous cross-linked, anionic and cationic
resins;
b) the resulting solution of step a) is added with
solid serinol at a temperature of 0-10°C and the
temperature is maintained for 5-20 h to give the
solution in dimethylacetamide of the compound of
20 formula (III), after basic treatment and after
removing most of the solvent through distillation
and diluted with water.
Using the process of this invention a synthetic
step is avoided, which allows the preparation of the
25 compound of formula (III) with a higher yield and in a
more profitable way from the industrial point of view.
In fact the isolation yield of the compound of formula
(II) is substituted with the chemical conversion of the
reaction equal to 96~ of the compound of formula (II).
20 The purification through the use of resins does not
produce the formation of by-products.
In addition there is an improvement in the
industrial production times since the isolation and
drying processes and the entire recovery of the solvents
25 in the reaction and precipitation are avoided.
The porous and/or macroporous cross-linked resins
used in step a) of the process of this invention, are
selected from the group constituted by: anionic cross-
linked resins, with a preferable polymer structure of
30 DVB acrylic (divinylbenzene), styrenic DVB, or
metaacrylic-DVB,used if anionic, in free base form, if

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cationic in sodium form.
The resins in step ay can be placed alone or in
9
series, or in mixed bed, in floating bed and the elution
is carried out under low or high pressure. The anionic -
5 and cationic resins have the following functional
characteristics wherein R is generally an alkyl group
which varies according to the selected resin type which
sometimes cannot be found in the suppliers' catalogue:
R
r
N~ R OH ~ N+ R~~ OH
1 ,
R H
strong anionic ~ ~ weak anionic
O
O\
~S~ Na
O
strong cationic
with sodium
and for instance are supplied by Rhom and Haas as
follows:
strong anionic Amberlyst~R~ A-26, A-29;
weak anionic Amberlyst~R~ A-21; Amberlite~R~ IRA 35;
PurolitetR~ A-830; Amberlite~R~ IRA 958;
Amberlite~R~ IRA 904;
cationic Amberlyst~R~ A-35; Amberlyst~R~ A-36;
Amberlyst~R~ XN 1010.
Resins with the same characteristics but supplied

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by other producers (for instance Lewatit, Dow etc.) can
also be used in the process of this invention.
t
Particularly preferred are the following resins
(supplied by Rhom & Haas) and the following arrangement
{for the amount of each bed please refer to the
Experimental Section):
- separate bed: a column containing Amberlyst{R) A-
21;
- separate bed: a column containing Amberlyst{R) A-21
followed by a second column containing Amberlyst(R)
A 26-OH-E;
- separate bed: a column containing Amberlyst(R) A-21
followed by a second column containing Amberlite(R)
IRA 35;
- mixed bed Amberlyst(R) A-22 and A-26-OH;
- floating bed Amberlyst(R) A-26-OH-E with solution
bottom loading;
- floating bed Amberlite(R) IRA 35 with solution
bottom loading;
- separate bed: a column containing Amberlyst(R)A-21
followed by a second column containing Amberlyst{R)
A-26-OH-E followed by a column Amberlyst{R) A-35
sodium regenerated.
It is important to hydrolyze 5-(-)-[2
(acetoxy)~propionic acid chloride in excess with water
to obtain the corresponding acid and hydrochloric acid,
so that the by-products can be kept on the
chromatographic columns.
This operation can be carried out by exploiting the
residual water present in the resin or by adding a water
content which can trigger the hydrolytic process which

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will continue on the resins.
In fact, despite the production of water, caused by
the desalinization of the anionic resin, in some cases
it is preferable to trigger the hydrolysis before the
step ~n r~~~ns.
The amount of water necessary for this reaction
ranges from 0 to 4 g for 100 g of the final reaction
solution of the compound of formula (II). The molar
amount of necessary water is calculated on the molar
excess of S-(-)-[2-(acetoxy)]propionic acid added for
the reaction to which the residual water content kept by
the resin is subtracted.
The amount of residual water on the resin can be
calculated on the amount of water in the solvent used
25 for the conditioning of the same.
It is extremely important to obstacle an excess of
water content to avoid the hydrolysis triggering of the
acyl chlorides of the compound of formula {II) due to
the alkalinity of the functional groups of the anionic
resins.
Therefore the water amount must be calculated
according to the type of resin used. Anyway the final
solution obtained after chromatographic purification
must have a residual water content of 0-2$ to avoid that
the addition of serinol triggers the hydrolysis of the
solvent or a part of the compound of formula (II) due to
serinol basicity.
This anhydrification can be carried out through
under-vacuum distillation or by keeping the solution at
the foreseen water limits.
In addition the resins used in the process of this

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invention are particularly useful for the purification
of dipolar aprotic organic solvents as for instance
dimethylformamide, N-methylpyrrolidone, acetamide,
dimethylsulphoxide, acetonitrile and in particular ,
dimethylacetamide or ester derivatives such as butyl
acetate, ethyl acetate, amyl acetate or isoamyl acetate.
In fact this solvent can be purified from organic
and inorganic iodinated pollutants thanks to the use of
porous/macroporous resins with an acrylic, metaacrylic
and styrenic polymer structure.
This technique is particularly useful in the case
where the solvent pollutants are organic and inorganic
salts and the hydrolysis products of the same solvent.
Particularly useful is the use of such techniques for
the solvent recovery in the synthesis of iodinated
contrast media where the solvent residual by-products
can be easily removed, thus avoiding complex extractions
or concentration and rectification systems and where the
solvent quality must be extremely high.
In addition this process is particularly useful in
the final removal of residual substances in any solvent
without performing rectifications which inevitably
reduce the recovery yields due to the elimination of the
first fraction condensed and the tail residual fraction
in the reboiler.
The resins can be used in anionic/cationic mixed
bed or in sequence of separate beds. In this case
cationic resins are used in a acid form while anionic
resins are used as free base.
Particularly preferred are the following resins and
arrangement:

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- mixed bed Amberlyst(R) A-35 and A-26-OH E;
- a column Amberlyst(R) A-35, a column Amberlyst(R)
A-29-OH and a column Amberlyst(R) A-35.
In this way a solvent with no residual substances
content starting from solutions containing 0.1~-4~ (w/w)
of inorganic chlorides and other ionic impurities can be
obtained.
The resins can be used with organic or hydroorganic
solutions with a water content ranging from 0.5$ (w/w)
to 90~ (w/w).
The solvent purification can be monitored through a
conductimeter to detect the resin activity during the
process.
In this case the value of specific conductivity
referred to 25°C, shifts from values of 20-25 mS/cm
to < 2 uS/cm.
The resulting solvent is then anhydrified through
distillation of residual water.
The following examples are aimed at illustrating
the best experimental condition to carry out the process
of this invention.
EXAMPLE 1
(S)-N,N'-bis[(2-hydroxy-1-(hydroxymethyl)ethyl]]-5-[(2-
hydroxy-1-oxopropyl]amino]-2,4,6-triiodo-1,3-benzendi-
carboxamide.
A) Preparation of a raw solution of (S)-5-[[2-
(acetyloxy}-1-oxopropyl]amino]-2,4,6-triiodo-1,3-
benzendicarboxylic acid dichloride in DMA.
700 g of (S)-(-}-5-amino-2,4,6-triiodo-1,3-benzen
dicarboxylic acid dichloride (prepared according to the
procedure described in patent GB 1472050} are dissolved,

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at room temperature and under stirring, in 1 kg of
dimethylacetamide.
288 g of (S)-{-)-[2-(acetyloxy)]propionic acid
chloride (prepared according to the procedure described
5 in GB 1472050) are added in 4 h and the temperature is
maintained at 3-5°C. The reaction terminates after being
kept for 30-40 h at a temperature of 6-15°.
B) Preparation of a raw solution of {S)-N,N'-bis[{2-
hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-
10 oxopropyl]amino]-2,4,6-triiodo-1,3-benzendicar-
boxamide.
680 g of a 42$ (w/w} solution A) are filtered to
remove the precipitated DMA hydrochloride and then
diluted with 310 g of DMA. 3.5 g of deionized water are
loaded to trigger the hydrolysis of (S)-{-}-[2
(acetyloxy)]propionic acid chloride, and the mixture is
kept under stirring for 30'. The resulting solution is
percolated on 1200 ml of anionic resin Amberlyst{R} A-21
with an exchange capacity of 1.25 eq/L, previously
anhydrified.
The resin is washed with 1000 ml of anhydrous DMA
and the resin residual product is completely removed.
DMA is distilled under vacuum at 70°C and 12 mmHg in
order to give a 20$ (w/w) solution of (S}-5-[[2-
(acetyloxy)-1-oxopropyl]amino]-2,4,6-triiodo-1,3-ben
zendicarboxylic acid dichloride equal to 1430 g.
152.3 g of solid serinol (commercial product) are
loaded and the temperature is kept under 5 °C. When the '
addition terminates the reaction mixture is kept under
stirring for 8 h at 10°C. Most of the reaction solvent
is distilled at 95°C and 10 mbar to give a viscous

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residue, which is diluted under heating with deionized
water.
The temperature of the resulting solution,
containing more than 99$ of the theoretical product, is
raised to 35C. 120 g of 30$ w/w sodium hydroxide are
added and kept under stirring for 7 h to produce the
saponification of acetic ester of the desired product,
that's to say (S)-N, N'-bis[(2-hydroxy-1-(hydroxy-
methyl)ethyl]-5-[(2-{acetyl)-1-oxopropyl]amino]-2,4,6-
triiodo-1,3-benzendicarboxamide. Then 50 g of 34$ w/w
hydrochloric acid are added to keep the pH at 6.5 to
terminate the sapanification and the resulting solution
of the desired raw product is then subjected to the
procedure described in patent GB 1472050.
Yield of the compound of formula {III) starting
from the compound of formula {I) - 75$
EXAMPLE 2
Alternative to EXAMPLE 1.
680 g of the raw solution A) of EXAMPLE 1 are kept
for 1 h at 0C and then filtered at the same temperature
by removing the precipitated DMA hydrochloride, then 410
g of DMA are added. 10.0 g of deionized water are loaded
to trigger the hydrolysis of (S)-{-)-[2-
(acetyloxy)]propionic acid chloride and the mixture is
kept under stirring for 30'.
The resulting solution is percolated on 800 ml of
anionic resin Amberlyst(R) A 21 and .with an exchange
capacity of 2.25 eq/L and 200 ml of strong anionic resin
Amberlyst{R) A-26-OH-E with an exchange capacity of 0.8
eq/L constituting a mixed bed of anionic weak/strong
resins and 50 ml of cationic resin Amberlyst{R) A-35

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with an exchange capacity of 1.9 eq/L regenerated with
sodium, previously anhydrified with DMA to give an
eluate with 0.5~ of residual water.
The resin is washed with 1500 ml of anhydrous DMA -
and the resin residual product is completely removed.
152.3 g of solid serinol are loaded following the
procedure of EXAMPLE 1.
Yield of the compound of formula (IIT) starting
from the compound of formula (I) - 80~
EXAMPLE 3
Alternative to EXAMPLE 1.
680 g of the raw solution A) of EXAMPLE 1 are kept
for 1 h at -5°C and then filtered at the same
temperature thus removing the precipitated DMA
hydrochloride, then 310 g of DMA are added. 2.5 g of
deionized water are loaded to trigger the hydrolysis of
(S)-{-)-[2-(acetyloxy)]propionic acid chloride and the
mixture is kept under stirring for 30'.
The resulting solution is percolated on 800 ml of
anionic resin Purolite(R) A-830 with an exchange
capacity of 2.7 eq/L previously anhydrified with DMA to
give an eluate with 1.5$ of residual water. The resin is
washed with 1000 ml of anhydrous DMA and the resin
residual product is completely removed. DMA is distilled
under vacuum at 70°C and 12 mmHg in order to give a 20$
(w/w) solution of (S)-5-jj2-(acetyloxy)-1-oxopropyl]- ,
amino]-2,4,6-triiodo-1,3-benzendicarboxylic acid
dichloride equal to 1430 g.
152.3 g of solid serinol are loaded following the
procedure of EXAMPLE 1.
Yield of the compound of formula (IIT) starting

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from the compound of formula (I) - 65~
EXAMPLE 4
Alternative to EXAMPLE 1.
680 g of the raw solution A ) of EXAMPLE 1 are kept
for 1 h at 0°C and then filtered at the same temperature
by removing the precipitated DMA hydrochloride, then 310
g of DMA are added. 15.0 g of deionized water are loaded
to trigger the hydrolysis of (S)-(-)-[2-(ace
tyloxy)]propionic acid chloride and the mixture is
maintained under stirring for 30'.
The resulting solution is fed from the column
bottom producing a floating bed of 1500 ml of anionic
resin Amberlite(R) IRA 35 with an exchange capacity of
2.0 eq/L. The resin is washed with 1500 ml of anhydrous
DMA and the resin residual product is completely
removed.
152.3 g of solid serinol are loaded following the
procedure of EXAMPLE 1.
Yield of the compound of formula {III) starting
from the compound of formula (I) - 55~
EXAMPLE 5
Alternative to EXAMPLE 1.
680 g of the raw solution A) of EXAMPLE 1 are kept
for 1 h at 0°C and then. filtered at the same temperature
thus removing the precipitated DMA hydrochloride, then
310 g of DMA are added. The resulting solution is fed
from the column bottom on 1500 ml of anionic resin
Amberlite(R) IRA 958 with an exchange capacity of 1.2
eq/L and 300 ml of cationic resin Amberlite{R) IRA 35
with an exchange capacity of 1.25 eqlL previously
anhydrified with DMA to give an eluate with 0.5$ of

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residual water. The resin is washed with 1500 ml of
anhydrous DMA and the resin residual product is
completely removed. DMA is distilled under vacuum at
70°C and 12 mmHg in order to give a 20$ (w/w) solution
of (S)-5-[[2-(acetyloxy)-1-oxopropyl~amino~-2,4,6-
triiodo-1,3-benzendicarboxylic acid dichloride equal to
1430 g.
152.3 g of solid serinol are loaded following the
procedure of EXAMPLE 1.
Yield of the compound of formula (III) starting
from the compound of formula (I) - 78~
EXAMPLE 6
Purification of DMA with porous/macroporous cross-linked
resins.
l5 5 1 of DMA solution di DMA with the following
analytical characteristics:
Chlorides = 3$
Mixture of 5-amino-2,4,6-triiodo-1,3-benzendicarboxylic
acid and by-products of mono- and diiodination = 5~
Specific conductivity = 24 mS/cm
Water = 65~
The solution is percolated on 600 ml of cationic
resin Amberlyst(R) A-35, and in series, on 1400 ml of
anionic resin Amberlyst(R) A-26-OH-E and on 150 ml of
resin Amberlyst(R) A-35.
An eluate with 10 uS/cm is given; no chlorides and
no triiodobenzoic acids are present. The solvent is
anhydrified through distillation under vacuum up to '
residue content < 0.5~.
Recovery yield > 90$

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EXAMPLE 7
DMA Purification with porous/macroporous cross-linked
resins.
5 1 of DMA solution with the following analytical
5 characteristics:
Chlorides = 2~
(S)-5-[[2-(hydroxy)-1-oxopropyl]amino]-2,4,6-triiodo-
1,3-benzendicarboxylic acid = 2~
Specific conductivity = 14 mS/em
20 Water = 5$
The resulting solution is percolated on a mixed bed
containing 600 ml of cationic resin Amberlyst(R~ A-35
and 2500 ml of anionic resin Amberlyst(R~ A 29 to give a
residual conductivity of 2.4 gS/cm; no chlorides and no
15 iodophthalic acids are present. The solvent is
anhydrified through distillation to give a water content
< 0.5$.
Recovery yield > 90~

Dessin représentatif