Note: Descriptions are shown in the official language in which they were submitted.
CA 02710570 2010-07-20
PN0956
Acetylation using reduced concentration of acetic acid anhydride for
synthesizing non-
ionic X-ray contrast agents
CROSS REFERENCE TO RELATED APPLICATIONS
The present application claims benefit of priority under 35 U.S.C. 119(e) to
United
States Provisional Application number 61/227,089 filed July 21, 2009, the
entire disclosure
of which is hereby incorporated by reference.
TECHNICAL FIELD
This invention relates generally to large-scale synthesis of non-ionic X-ray
contrast
agents. It further relates to an improved method for the synthesis of 5-
acetamido-N,N'-
bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide ("Compound A"), an
intermediate in
the industrial preparation of non-ionic X-ray contrast agents. In particular,
it relates to
acetylation of 5-amino-N, N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-
benzenedicarboxamide ("Compound B") using reduced concentration of acetic
anhydride.
BACKGROUND OF THE INVENTION
Non-ionic X-ray contrast agents constitute a very important class of
pharmaceutical
compounds produced in large quantities. 5-[N-(2,3-dihydroxypropyl)-acetamido]-
N,N'-
bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide ("iohexol"), 5-[N-(2-
hydroxy-3-
methoxypropyl)acetamido]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-
isophthalamide
("iopentol") and 1,3-bis(acetamido)-N,N'-bis[3,5-bis(2,3-dihydroxypropyl-
aminocarbonyl)-
2,4,6-triiodophenyl]-2-hydroxypropane ("iodixanol") are important examples of
such
compounds. They generally contain one or two triiodinated benzene rings.
In particular, iodixanol, marketed under the trade name Visipaque , is one of
the
most used agents in diagnostic X-ray procedures. It is produced in large
quantities by GE
Healthcare in Lindesnes, Norway. The industrial production of iodixanol
involves a
multistep chemical synthesis as shown in Scheme 1 below. To reduce the cost of
the final
product, it is critical to optimize each synthetic step. Even a small
improvement in reaction
design can lead to significant savings in a large scale production.
The instant improvement is directed to the acetylation step, where 5-amino-
N,N'-
bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (Compound B) is
acetylated to produce
5-acetylamino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide
(Compound A)
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PN0956
using acetic anhydride as the acetylating reagent. According to the present
invention, the
concentration of acetic anhydride used in the acetylation reaction is
significantly reduced.
OH
HO O CH3o O 1-amino-2,3- HO N O
CH3OH / propanediol
-~ ~
CH30 OH &NO / HO
\ I NO2 NO z HO / , N O OH OH
H2 "0 \i N O HO N O
z 10 Acetic
OH OH I / 1 Anhydride
-' / -y
HORN HO~, N
NH2 NH 2
O O I
Compound B
OH
H OH OH
HO N O Epichloro- HO '-J-11 N 0 0 N i OH
OH 1 / 1 hydrin
H I OH I I OH
HO N NH HO ~i N N- N N OH
O 1 O'J' 0 I OHO 1 0
Compound A
lodixanol
Scheme 1
SUMMARY OF THE INVENTION
The present invention provides an industrial process for preparing Compound A
by
acetylation of Compound B. Specifically, it uses about 50 v/v % to about 85
v/v % acetic
anhydride and about 15 v/v % to about 50 v/v % acetic acid as a reagent
mixture. In a
preferred embodiment, following the acetylation reaction, the reagent and
solvent mixture is
distilled for re-use in a subsequent acetylation reaction from Compound B to
Compound A.
DETAILED DESCRIPTION OF THE INVENTION
In the acetylation reaction of Compound B, both the amino group and the
hydroxyl
groups are acetylated. While the hydroxyl groups are later deacetylated by the
addition of
aqueous sodium hydroxide, a full acetylation of Compound B involves the
addition of six
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CA 02710570 2010-07-20
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acetic anhydride equivalents (four 0-acetyls and two N-acetyls from four
hydroxyl groups
and two amino hydrogens respectively). See Scheme 2. Traditionally, the lowest
concentration of acetic anhydride in the reagent and solvent mixture of acetic
anhydride and
acetic acid used in the acetylation reaction has been about or over 90% (v/v).
HO OH HO OH
NH O 0 NH
O I )L O O I
I NH2 I NH
HO NH I HO NH I
HO HO
Scheme 2
We have now surprisingly found that less concentration of acetic anhydride in
the
acetic anhydride and acetic acid mixture can be used in the acetylation
reaction to allow for
nearly full conversion from Compound B to Compound A. In particular, the
necessary
conversion of Compound B to Compound A can be obtained with between about 50 %
(v/v)
and about 85 % (v/v) of acetic anhydride, without increasing the total
combined volume of
acetic anhydride plus acetic acid.
It has been found that a total acetylation degree of at least 5.0 is required,
since the
hydroxyl groups are slightly more reactive than the amino group, and a full
conversion to at
least one aminoacetyl group is necessary to effect a full net conversion to
Compound A after
deacetylation. Specifically, in the deacetylation step, saponification of the
acetoxy groups are
more easily obtained than hydrolysis of the aminoacetyl group(s), making it
possible to retain
one aminoacetyl group unhydrolysed by optimizing the pH in the deacetylation
step, thus
obtaining Compound A in high purity. The deacetylation step may be performed
after
dilution of the process solution with methanol and water. Compound A may be
crystallised
from the deacetylated solution by the addition of hydrochloric acid followed
by filtration,
wash of the filter cake with a suitable solvent, e.g. methanol, and drying in
a suitable dryer.
After the acetylation reaction excess acetic anhydride and acetic acid may be
distilled
for re-use. In particular, the distillation process may be performed under
reduced pressure.
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Preferably, a fraction of the distillate may be re-used in the next batch of
acetylation reaction
and mixed with fresh acetic anhydride to form the desired concentration in the
desired total
amount of reagent and solvent. More preferably, the excess mixture of acetic
anhydride and
acetic acid is distilled and collected continuously. For example, earlier
portions of the
distillate have a much higher content of acetic acid than latter portions
because acetic acid
has a lower boiling point than acetic anhydride (118 C vs. 136 C at
atmospheric pressure).
As such, the latter portions of the distillate may be suitable for
regeneration and re-use
purposes because of their high acetic anhydride content. The split between non-
useable and
reusable distillate is determined by the mass balance for acetic anhydride and
acetic acid,
where the acetic acid content reaches a level where it is stoichiometrically
impossible to
obtain an acetylation degree of 5.0 (see above).
The instant invention provides several distinct advantages. First, the amount
of
expensive acetic anhydride consumed per batch is reduced. Because acetic acid
is cheaper
than acetic anhydride, the replacement of acetic anhydride with acetic acid
lowers the reagent
cost and in turn drives down the overall production cost for the drug
substance. The cost of
manufacture is further lowered because energy costs are reduced because the
fraction of
acetic acid vs. acetic anhydride in the distillate is significantly increased
and acetic acid has a
lower boiling point than acetic anhydride.
Second, acetic acid is easier to handle because it is much less reactive than
acetic
anhydride.
Finally, the fraction of distillate that is suitable for regeneration and re-
use is
drastically increased. Specifically, with more acetic acid content used in the
acetylation
reaction, more of the distillate can be re-used. This is because, as discussed
above, earlier
fractions of the distillate, which are rich in acetic acid, can be reused
(without reaching the
point where the mass balance disturbs the stoichiometry).
The invention is illustrated further by the following examples that are not to
be
construed as limiting the invention in scope to the specific procedures
described in them.
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EXAMPLES
EXAMPLE 1 (Comparative Example)
Acetic anhydride (240 mL) and regenerated acetic anhydride (containing about
50-55
v/v % acetic acid) (60 mL) were mixed in a reactor, giving a mixture
containing 90 v/v %
acetic anhydride and 10 v/v % acetic acid, which corresponds to 2.85 mole of
acetic
anhydride. Compound B (200 g, 0.28 mole) was added at ambient temperature and
the
mixture heated to 55 C. Then, p-toluene sulphonic acid (1.0 g, 0.0058 mole)
was added and
the mixture further heated to 120 C over one hour. The acetylation degree was
measured by
HPLC to be 5.41. In other words, on average, 5.41 of 6 potential groups that
can be
acetylated in each molecule of Compound B have been acetylated.
EXAMPLE 2
Acetic anhydride (150 mL) and regenerated acetic anhydride (containing about
50-55
v/v % acetic acid) (150 mL) were mixed in a reactor, giving a mixture
containing 75 v/v %
acetic anhydride and 25 v/v % acetic acid, which corresponds to 2.38 mole of
acetic
anhydride. Compound B (200 g, 0.28 mole) was added at ambient temperature and
the
mixture heated to 55 C. Then, p-toluene sulphonic acid (1.0 g, 0.0058 mole)
was added and
the mixture further heated to 120 C over one hour. The acetylation degree was
measured by
HPLC to be 5.25. In other words, on average, 5.25 of 6 potential groups that
can be
acetylated in each molecule of Compound B have been acetylated.
EXAMPLE 3
Acetic anhydride (40 mL) and regenerated acetic anhydride (containing about 50-
55
v/v % acetic acid) (260 mL) were mixed in a reactor, giving a mixture
containing 54 v/v %
acetic anhydride and 46 v/v % acetic acid, which corresponds to 1.72 mole of
acetic
anhydride. Compound B (200 g, 0.28 mole) was added at ambient temperature and
the
mixture heated to 55 C. Then, p-toluene sulphonic acid (1.0 g, 0.0058 mole)
was added and
the mixture further heated to 120 C over one hour. The acetylation degree was
measured by
HPLC to be 5.04. In other words, on average, 5.04 of 6 potential groups that
can be
acetylated in each molecule of Compound B have been acetylated.
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All patents, journal articles, publications and other documents discussed
and/or cited
above are hereby incorporated by reference.
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