Note: Descriptions are shown in the official language in which they were submitted.
CA 02710090 2010-07-20
PN0955
Acetylation using reduced volume 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 61/227,087 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 a reduced amount of acetic anhydride
and
acetic acid as a reagent and solvent mixture.
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 I 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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PN0955
using acetic anhydride as the acetylating reagent. See Scheme I below.
According to the
present invention, the reagent volume as well as the solvent volume used in
the acetylation
reaction are significantly reduced.
OH
HO O CH3O O 1-amino-2,3- HO ) N H
O
CH3OH propanediol
OH
HO &NO 2 CH3O O NO z HO,, N N02
O o
O}1 OH
H
H2 HO "ill N O IC HO,_,~N O
Acetic
OH OH H I I Anhydride
HO N NH 1-10 N I NI12
z
0 0 1
Compound B
OH
11
110N 0 OH H H Oil
Epichloro- HO 'A, N O O N OH
OH 1,/ hydrin I I I I
~ N OH Oil
1 10 N NH HOBiN H F]
\ N~N \ N,J,, OH
O I
O 0 1 OII I 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 between about 1.5 and about
3.0 liter of
acetic anhydride and acetic acid as a reagent and solvent mixture per kilogram
of Compound
B. In a preferred embodiment, following the acetylation reaction, the reagent
and solvent
mixture are distilled for re-use in a subsequent acetylation reaction from
Compound B to
Compound A.
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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
acetic anhydride equivalents (four 0-acetyls and two N-acetyls from four
hydroxyl groups
and two amino hydrogens respectively). See Scheme 2. Typically, acetic
anhydride is also
used as the solvent in the acetylation reaction to avoid introducing an
additional component
in the system. In such a design where no other solvent is present, the volume
of acetic
anhydride in the acetylation reaction typically exceeds more than 3.0 L per
kilogram of
Compound B.
HO OH HO OH
NH~ O O NHY
O 1 O/ O
I NH2 I NH
I= O
HO NH PI HO NH 1
HO HO J-j
Scheme 2
We have now surprisingly found that such high amount of acetic anhydride is
not
required to complete the acetylation reaction. The reaction can be led to
completion using a
blend of acetic anhydride and acetic acid with the latter as a solvent. In the
instant method,
the volume requirement for reagent and solvent in the acetylation reaction can
be
significantly reduced from the volume of acetic anhydride that has been
previously used.
Specifically, a combined volume of acetic anhydride and acetic acid between
about 1.5 and
about 3.0 liter per kilogram of Compound B can be safely and effectively
operated to
complete the acetylation reaction. In a preferred embodiment, the volume range
is about 1.5
and about 2.0 liter of acetic anhydride and acetic acid per kilogram of
Compound B.
Under the present procedure, the acetylation reaction solution is still
stirrable. The
exothermic nature in the acetylation reaction can be handled safely, and a
full conversion
from Compound B to Compound A may be obtained. The combination of acetic
anhydride
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and acetic acid further allows the excess reagent and solvent mixture to be
regenerated and
re-used in another batch of acetylation reaction.
The temperature of the reaction is typically in the range of about 50 to about
125 C,
gradually increasing as the exotherm in the reaction heats the reaction
mixture. In certain
embodiments, the acetylation reaction is preferably started at ambient
temperature. An acid
catalyst, such as sulphuric acid or p-toluene sulfonic acid, may also be added
in the
acetylation reaction.
The instant invention provides several distinct advantages. First, the amount
of
expensive acetic anhydride consumed per batch is reduced. In addition, because
acetic acid is
cheaper than acetic anhydride, the partial replacement of acetic anhydride
with acetic acid
lowers the reagent cost and in turn drives down the overall production cost
for the drug
product.
Second, the cost of manufacture is further lowered because energy costs and
process
time are reduced due to less volume of acetic anhydride and acetic acid to be
processed after
the acetylation reaction.
Finally, the instant method allows for a substantial amount of the excess
acetic
anhydride and acetic acid to be regenerated and re-used after the completion
of the
acetylation reaction. In a traditional approach where only acetic anhydride is
used without
acetic acid, reagent regeneration is impractical. Specifically, if pure acetic
anhydride is used
in the reaction, it is necessary to carry out each batch of acetylation with
100% acetic
anhydride. Thus, any regeneration of excess acetic anhydride requires a
complete separation
of acetic anhydride from acetic acid, the inevitable byproduct of the
acetylation reaction (one
mole of acetic anhydride gives one mole of acetylated product and one more of
acetic acid).
This separation involves a series of difficult and expensive processes.
The instant process, on the other hand, begins with the use of a mixture of
acetic
anhydride and acetic acid as a reagent and solvent mixture in the first batch
and continues to
use a mixture of acetic anhydride and acetic acid in subsequent batches. Thus,
excess acetic
anhydride and acetic acid are mixed with acetic acid byproduct from the
acetylation reaction
and the remixed acetic anhydride and acetic acid can be selected for
regeneration and re-use
for new batches of acetylation reaction. For example, after the acetylation
reaction, excess
acetic anhydride and acetic acid may be regenerated by distillation because
acetic acid has a
lower boiling point than acetic anhydride (1 l 8 C vs. 136 C at atmospheric
pressure). As
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shown in the examples below, 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
total amount of
reagent and solvent mixture.
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 or
products described
in them.
EXAMPLES
EXAMPLE 1
Compound B (5356 kg) was suspended in a mixture of acetic anhydride and acetic
acid (10900 L, 2.0 L/kg Compound B, 91 v/v % acetic anhydride and 9 v/v %
acetic acid) at
ambient temperature. This mixture was prepared by mixing acetic anhydride
(8115 kg) and
regenerated acetic anhydride (3460 kg), the latter containing 66 v/v % acetic
anhydride and
34 v/v % acetic acid obtained from a previous batch. The mixture was heated to
55 C. Then,
p-toluene sulfonic acid (25 kg) was added and the reaction mixture was further
heated to
117 C over about 90 minutes. All solids were dissolved in the reaction, and
100 % of
Compound B was acetylated. The remaining acetic anhydride/acetic acid (8430 L)
was
distilled off under reduced pressure resulting in a highly viscous reaction
mixture. Forty-one
percent of the distillate could be re-used as reagent in a later batch without
a discrete
purification step.
EXAMPLE 2
Compound B (5356 kg) was suspended in a mixture of acetic anhydride and acetic
acid (7760 L, 1.45 L/kg Compound B, 87 v/v % acetic anhydride and 13 v/v %
acetic acid) at
ambient temperature. This mixture was prepared by mixing acetic anhydride
(6086 kg) and
regenerated acetic anhydride (2295 kg), the latter containing 48 v/v % acetic
anhydride and
52 v/v % acetic acid obtained from a previous batch. The mixture was heated to
55 C. Then,
p-toluene sulfonic acid (25 kg) was added and the reaction mixture was further
heated to
124 C over about 90 minutes. All solids were dissolved in the reaction, and
100 % of
Compound B was acetylated. The remaining acetic anhydride/acetic acid (5580 L)
was
distilled off under reduced pressure resulting in a very viscous reaction
mixture. Thirty-nine
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percent of the distillate could be re-used as reagent in a later batch without
a discrete
purification step.
All patents, journal articles, publications and other documents discussed
and/or cited
above are hereby incorporated by reference.
G
