Note: Descriptions are shown in the official language in which they were submitted.
~U~U4~9
NOpEI. CARBO%AN(IDE NON-IONIC
CONTRAST 1~~EDIA
INTRODUCTION
Technical Field
The field of the invention is methods of
preparation and compositions for use as non-ionic
contrast media.
Background
Radiographic contrast media for~visualization
of the cardiovascular system and body cavities must
have low viscosity, be highly water soluble, non-toxic,
and have a high iodine content. Low viscosity is
imperative for rapid delivery, to momentarily replace
rapidly flowing blood, such as in cardioangiography or
high dose urography, or contrast enhancement in
computerized tomography. To be non-toxic, the compound
must be highly hydrophilic, non-ionic, and of
osmolality close to the body milieu. While the non-
ionic monomeric media of the prior art have a
reasonable biological tolerance and useful viscosity,
they are hyperosmolal vis-a-vis the body milieu.
Typically, at the diagnostically useful concentration
of 300 mg I/ml, they substantially exceed the
physiological value of 310 mOsm. Hyperosmolality of
these solutions necessarily drives water out of cells,
disrupting the cellular membranes, perturbing the
CA 02020489 2003-12-30
2
overall electrolytic balance, and damaging the lining
of vessels or of organ cavities. Also, hyperosmalality
has been shown to be one cause of vascular pain
invariably elicited by hyperosmolal contrast media.
Most of the non-ionic contrast media, whether
monomeric or oligomeric, are aromatic amides, with one
or more polyhydroxy, lower aliphatic alkyl, and acyl
subgroups bonded to nitrogen, with annular carboxamides
and amino groups. The triiodinated benzene ring
contains a number of functionalities in close spatial
relationships. The prior art describes several
hydroxyalkylamines attached as amides. Examples of
these amines include: serinol; 1-amino-2,3-
propanediol; N-methyl 1-amino-2,3-propanediol;
aminotetritols; ethanolamine, diethanolamine, or
tromethamine.
Substitution of the carboxyl groups in the 1
and 3 positions with the same hydroxyalkylamine poses a
severe limitation on the design, since the
substitutents practically available are either too
small to solubilize the molecule, or too large to
result in a solution of low viscosity (Nycomed, U.S.
4,021,481 and 3,701,771; Schering AG, O.S. 4,547,357
Bracco, U.S. 4,001,323). For this reason, improved
compounds were developed where the two hydroxyalkyl-
amines were different (Schering AG O.S. 4,364,921).
Such compounds, however, have a complex synthesis and
are costly to synthesize.
Relevant Literature
U.S. Patent Nos. 3,701,771, 4,001,323,
4,021,481, 4,364,921, 4,547,357 and 4,954,348 are
illustrative of various compounds reported as useful
for non-ionic contrast media.
CA 02020489 2003-06-10
3
SUMMARY OF THE ~N'VENTICIN
Non-ionic contrast media are provided based on
an asymmetrical triiodoisophthalic diamide, where the
remaining rang position is occupied by a substituted
nitrogen, one of the carboxyl groups being
unsubstituted amide, and the other carboxyl. groups
being at least a mono-(hydroxyalkyl) substituted
amide. The molecule has at least two hydroxyl.
groups.
DESCRIPTTON OF SPECTFIC EM80DIS
Non-ionic contrast media are provided based on
an acylamido substituted triiodoisophthalic diamide,
where only one of the amide nitrogens is at least
monosubstituted. The compounds may be inexpensively
synthesized in good yield and obtained in high purity..
The subject compounds have been found to provide low
osmalality~ while at the same time maintaining moderate
to low viscosity.
The compounds of the subject invention will
for the most part have the following Formula (I):
CONH2
T ~Z
R3COt~ '--r' Ct~NRIRZ
R4 I
I
wherein:
R1 is hydrogen, lower alkyl or
hydroxyalkyl, v~herei.n the alkyl group is from 1 to
6, preferably 1 to 3, usually ~ to 2 carbon atoms,
and the hydroxyalkyl group has at least tJ.S
hydroxyls per carbon atom and up to r~~~. hydroxyl
~o~o~~~
groups, where n is the number of carbon atoms, hydroxyalkyl being
from 2 to 6, usually 2 to 4 carbon atoms;
R2 is a mono- or polyhydroxyalkyl, of from 2 to 6, usually 2 to 4
carbon atoms, having at least one hydroxyl group and not less
than n-2 and not more than n-1 hydroxyl groups, where n is the
number of carbon atoms;
R3 is lower alkyl, hydroxy (lower alkyl), or lower alkoxy (lower
alkyl), where alkyl is from 1 to 4 carbon atoms, usually of from
1 to 3 carbon atoms, and alkoxyl is of from 1 to 3, usually 1 to
2, carbon atoms, with the number of oxy groups varying from 0 to
n-1, where n is the number of carbon atoms, or two Rg groups may
be taken together to define a bridge of from 0 to 2 carbon atoms,
preferably 1 carbon atom; i.e., R3 represents
2
I I
-(CtI')C-2-CON CONR1R2
Rq I
R4 is hydrogen, lower alkyl, or mono- or polyhydroxyalkyl, where
the alkyl groups and the hydroxyl groups come within the
definitions as described above for analogous groups.
The alkyl groups may be straight chain or branched, usually
straight chained where carbon atoms will normally be other than
quaternary.
The alkyl residue in the mono- or polyhydroxyalkyl R1 and R2 will
usually have 2 to 6 carbon atoms, usually 2 to 4 carbon atoms.
Preferably, the groups will have 1 to 5, usually 1 to 3 hydroxy
groups. These hydroxy groups may be primary, secondary, or
- 4 -
tertiary. Examples include trishydroxymethylmethyl,
hydroxyethyl, dihydroxypropyl, and trihydroxybutyl. Carbamides
may be prepared using 3-amino-1, 2-propanediol, serinol or amino-
tetritols, i.e., threitol and erythritol, either in D,L mixture
or optically pure forms, ethanolamine, or diethanolamine, or
tromethamine, or derivatives thereof, where the hydroxyl groups
are reversibly protected. R1 is hydrogen, or lower alkyl,
preferably hydrogen or
- 4a -
~~~~~~9
,
methyl. R3 is a lower alkyl or oxya:Lkyl of 1 to 6,
usually 1 to 4 carbon atoms, preferably methyl,
hydroxymethyl or hydroxyethyl. Also exemplified are
alkoxyalkyls containing alkoxyl groups of 1 to 3 carbon
5 atoms, preferably 1 to 2 carbon atoms, and alkyls of
from 1 to 3 carbon atoms, more particularly
methoxymethyl. Alternatively, two R3 groups are taken
together to be a bond, methylene or ethylene,
particularly methylene. R4 is hydrogen, alkyl or mono-
or polyhydroxyalkyl of from 1 to 6, usually 1 to 4,
carbon atoms, including methyl, ethyl, propyl,
hydroxyethyl, and dihydroxypropyl.
Monomeric compounds of interest include 5-[N-
(2-hydroxyethyl)methoxyacetamido]-2,4,6-triiodo-3-[N-
(1,3,4-trihydroxybut-2-yl)]carbamoyl benzamide; S-[N-
(2-hydroxyethyl)hydroxyacetamido]-2,4,6-triiodo-3-[N-
(2,3-dihydroxypropyl)]carbamoyl benzamide: 5-[N-(2,3-
dihydroxypropyl)acetamido]-2,4,6-triiodo-3-[N-(2,3-
dihydroxypropyl))carbamoyl benzamide; 5-[N-(2,3-
dihydroxypropyl)glycolamido]-2,4,6-triiodo-3-[N-(2-
hydroxyethyl)]carbamoyl benzamide; 5-(N-(1,3,4-
trihydroxy-but-2-yl)acetamido]-2,4,6-triiodo-3-[N-(2-
hydroxyethyl)]carbamoyl benzamide; 5-[N-
(methyl)glycolamido]-2,4,6-triiodo-3-[N-(1,3,4-
trihydroxy-erythro-but-2-yl]carbamoyl benzamide: and
5-[N-(2-hydroxyethyl)acetamido]-2,4,6-triiodo-3-[N-
(1,3,4-trihydroxythreobut-2-yl)]carbamoyl benzamide.
Dimeric compounds of interest include malonic
acid bis-l~3-N-(2,3-dihydroxypropyl-carbamoyl)5-carbamoylj-
2~1~~6-triiodo-N-(2,3-dihydroxypropyl); malonic acid
bis-~_i3-N-(2,3-dihydroxypropyl-carbamoyl)5-carbamoylJ-
2,4,6-triiodo-N-(2-hydroxyethyl)anilide; and malonic
acid bis-~~3-N-(~,3,4-trihydroxy-but-2-yl-carbamoyl)-
5-carbamoylf-2,1l,6-triiodo-N-methyl anilide.
The compositions of the subject invention will
have from about 50 to 52~ iodine, usually about 51~,
6
have a viscosity of a solution of 300 mg I/ml at 37°C
(cps) in the range of about 4 to 5, and an osmolality
of 300 mg I/ml at 37°C in mOsm for an aqueous solution
in the range of about 275 to 400, more usually about
285 to 375, while with a pharmaceutical formulation, it
will range from about 300 to 400, more usually about
325 to about 390.
The subject compositions are formulated in
accordance with conventional conditions. Usually, the
formulations will comprise an aqueous medium, which
includes a physiologically acceptable chelated calcium
salt, e.g., EDTA, a buffer to provide a pH in the range
of about 6.5 to 7.5, particularly about 7, where the
buffer may include tris, carbonate, citrate, or
combinations thereof. Other additives which may be
included are bicarbonate, phosphate, etc. The chelated
calcium will generally be present in from about 5 to
15, usually about 10 mg/100 ml, while the buffer will
generally be present in the amount from about 2 to 10
mM.
Conventional reactions may be combined in a
defined pathway to prepare the subject compounds.
Thus, in a subject process, the products of this
invention can be prepared, for example, from the
compound of Formula (II):
COX
R1
02N CONS
R2
II
where R1 and R2 are as defined previously, and
X is either a lower alkyl ester or a halogen.
7
Compounds under general Formula (II) a.re prepared by
reacting an hydroxyalkylamine (NHR1,R2,) whose OH groups
are protected or unprotected, with a commercially
available monoester of 5-nitroisophthalic acid,
followed by activation of the remaining carboxyl
group. Such activation is suitably achieved when X is
a halogen such as C1, Hr, I, or alkoxy with chlorine
and methoxy being preferred.
The ester group of 5-nitroisophthalic acid,
mono-ester is aminolyzed with the hydroxyalkylamine of
general formula HNR1R2 as defined above, or aminolysis
can be achieved with ammonia first. The remaining
carboxyl group is then activated as described above.
If the hydroxyl groups of the residue NR1R2 are
1S unprotected and could be affected by the activation,
they can suitably be protected by conventional means
such as 0-acetylation or by isopropylidination.
The compound of general Formula (II) can be
conveniently crystallized from water or lower alcohols.
After reaction with anhydrous ammonia or
ammonium hydroxide, where the asyimnetrical
isophthaldiamide is obtained, the compound is
hydrogenated. triiodinated and acylated in a
conventional manner to arrive at general Formula (III):
CONH2
1 1
R1
R3COHN CON'
I
III
R2
where R1, R2, and R3 are defined as above.
Reduction and iodination is typically carried
8
out by standard methods using as catalysts, palladium
on carbon or Raney nickel in water or lower alcohols,
and hydrogen under low or high pressure. The resulting
5-aminoisophthalic acid bisamide is then iodinated by
known methods. The compound is then conveniently
recovered as it crystallizes from the reaction mixture,
washed, dried, and subjected to acylation, also
following known methods. Thus, an activated aayl
R3C0--X, where X is halo or the same acyl group to form
an anhydride, and catalyzing solvents such as pyridine,
DMA, or DMF may be used.
If compounds according to Formula (I), where
R4 is other than hydrogen, are prepared, the alkylation
is carried out by standard methods. Except for lower
alkyls which are conveniently introduced at an earlier
stage of the synthesis, the reaction with hydroxyalkyl
residues is carried out typically as the last step.
Such an alkylation can be carried out in a high boiling
glycol solvent, such as ethylene or propylene glycol,
and highly basic pH achieved with sodium methoxide,
sodium hydroxide, or other inorganic or organic bases.
Alternatively, it is sometimes advantageous
for the purposes of purification where side products
are formed which would otherwise be difficult to remove
by conventional purification methods, to maintain the
presence of one carboxyl group until the latter stages
of the reaction sequence, so that the compound can
conveniently be dissolved in water as a salt and
thereafter precipitated or reprecipitated with an
inorganic acid. Preferred salts include ammonium,
sodium, potassium, calcium, barium or lithium.
Such alternative process is based on the
reduction, iodination and acetylation of compounds of
Formula (II) (where X = OH) in the manner described
above to arrive at Formula (IV):
9
COON
I I
R1
R3COHN CONS
R2
I
IV
where Rl, R2 and R3 are defined above.
The hydroxyl groups are protected prior to
activation of the carboxyl group. It is also necessary
to diacylate the anilide with R3C0, as this nitrogen
would likewise be adversely affected during carboxyl
activation. The carboxyl group will be activated as
described above, with the acid chloride being
preferred, although mixed anhydrides may be used, e.g.,
_t-butyloxycarbonyl. Compounds under Formula (IV) can
conveniently be crystallized from an aprotic solvent
and reacted with ammonium hydroxide or ammonia,
followed by alkylation as the last step.
Effective amidation usually requires use of
either an excess of amidating base as an acid acceptor
or alternatively, tertiary amines, such as
triethylamine, tributylamine, pyridine, or inorganic
bases such as bicarbonate or carbonate.
Yet another variation of the synthetic process
can be applied when undesirable side products occur.
Thus, alkylation of the anilide may be carried out
prior to the amidation. Alkylation of the compounds
under general Formula (IV), where Rl, R2, and R3 are as
defined above may be carried out by known methods as
described above.
During alkylation to introduce R4, the
protecting groups R3C0 are lost, and thus the hydroxyl
groups of Rl and R2 (also R4 if present) must be
10
re-protected prior to carboxyl activation and
subsequent amidation with ammonia. Acetyl groups are
most often employed for this purpose.
Following the final step, if hydroxyl groups
are still protected, such as would be the case when
alkylation is not carried out as the last step, the
protecting groups may conveniently be removed by
standard means such as exposure to ion exchange resins,
or use of acids or bases in catalytic amounts in
alcoholic or aqueous solvents.
Desalting can be accomplished by known
methods. Typically, salts will be removed by ion
exchange resins, either mixed-bed or in separate
columns individually containing an anionic or cationic
exchange resin. Alternatively, the compounds of
general Formula (I) can be absorbed on a polystyrene-
absorbing neutral resin and thereafter eluted.
Following removal of the salts, the product
can now be crystallized from a variety of solvents,
preferably lower alcohols. Decolorization is achieved
by refluxing in aqueous solution with activated
charcoal.
The diner is conveniently prepared from the
benzamide, with the amino nitrogen alkylated and the
remaining carbonyl group activated, e.g., chloro-
carbonyl. The dibasic acid is used in activated form,
particularly as the diacyl dichloride in an organic
aprotic polar solvent. The ring carbon bound
chloracarbonyl is then hydroxyalkylamidated to obtain
the final product.
The compounds of this invention and under
general Formula (I) are stable in aqueous solutions;
they readily form supersaturated solutions which also
remain stable. The solutions can be autoclaved by
standard means. At diagnostically useful iodine
concentrations, the compounds have osmolalities which
typically are very close to the physiological values.
At the same, time, the solution viscosity is low. Thus, the
objective of this invention to overcome the previously recognized
mutual exclusivity o:E the two factors, i.e., low osmolality and
low viscosity, has been accomplished. As a result, the novel
compounds have excellent local and systemic tolerance. The
compounds have good biological tolerance and high iodine content,
particularly as compared to presently available non-ionic
radiographic contrast media.
As examples of the properties of the benzamide class compounds,
data were generated for the compounds (11) and (19). For
comparison, data on prior art compounds are also shown in Table
I.
- 11 -
~~~~4~~
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11
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cn b N r
a~ Ix .--i
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CT O I c~'1
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H r-1 .-I .-1
ro r-, I I I I . I
I
1-~ t0 rl N ri rr1:f~ W
p O N
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4l
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p, o r Wn co ~o I r
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13
The observed low osmolality and concurrent low
toxicity was only previously achieved in non-ionic
dimers, which, however, cannot be utilized in general
uroangiography due to their high viscosity which, for a
comparable solution concentration, is at least two
times higher.
The novel compounds show an excellent general
biological tolerance. Since high osmolality is the
causative factor of vascular pain and a major side
effect of depicting the peripheral limb vasculature
(Sovak, M., Current Contrast Media and Ioxilan,
Comparative Evaluation of Vascular Pain by Aversion
Conditioning, Investigative Radiology, September, 1988
Supp). This is one of the major diagnostic procedures
in vascular radiology. The novel compounds of this
invention are expected to be virtually painless in such
procedures. Because of their physiochemical and
pharmacological properties,.the novel compounds are
suitable as water-soluble contrast media for the
visualization of the urine excretory and cardiovascular
systems, and body cavities and for general contrast
enhancement in computerized tomography. The injectable
solutions of the novel compounds can be prepared by
dissolution in water and adding standard physiological-
compatible buffers, and stabilizers such as chelating
agents. The compounds also are suitable for enteral
application when formulated with carriers usually
employed in the pharmacopoeias. The dimers find
particular use for myelograms.
For intravascular use, the compounds of this
invention contain 20%-80% weight by volume, with iodine
concentrations of 150 to 400 mg/ml preferred.
The following examples are offered by way of
illustration and not by way of limitation.
14
cwocv Tra~a~mar.
EXAMPLE 1
Amidation of 5-nitroisoph~thalic
acid, monomethyl ester (1) with
(threo)-2-amino-1,3,4-butanetriol
into: 5-nitro-3{N-(1,3.4-trihydroxy-
threo-but-2~r1)~carbamo~l benzoic acid (2)
The starting material (1, 22.5 g, 0.1 mole)
was mixed with (threo)-2-amino-1,3,4-butanetriol (30.25
g, 0.25 moles) and the suspension heated to 110-120°C
for 30 min. Complete conversion to the product was
seen by TLC and the solution was poured into 1 N
hydrochloric acid (200 ml) to precipitate the product.
After cooling overnight. the product was filtered and
washed with ice-cold water (20 ml x 2). Drying in
vacuo gave a white solid (2, 21.0 g, 67t yield).
EXAMPLE 2
Esterification of 5-nitro-3{N-(1,3,4-
trihydroxy-threo-but-2-yl)}carbamoyl benzoic
acid (2) with dimethyl sulfate into:
methyl 5-nitro-3{N-(1,3,4-trihydroxy-
_threo-but-2-yl)}carbamoyl benzoate (3)
The title compound (2, 15.7 g. 0.05 moles) was
dissolved in 1 N sodium hydroxide solution (55 ml) and
the solution cooled to < 20°C. Dimethylsulfate (9.45
g, 0.075 moles) was added over 5 min and the pH was
maintained between 8-10 by the occasional addition of 5
N sodium hydroxide solution. The solution was stirred
for ca. 12 hr at room temperature after which the
insoluble solid was filtered off. The pasty solid was
washed with cold water (50 ml x 2) and was dried in
vacuo to give a powder (3, 11.8 g, 72~ yield).
15
E~A~PLE 3
Amidation of methyl 5-nitro-3-j,N-(1,3,4-
trihydroxy-threo-but-2-yl)}carbamoyl benzoate
(3) with ammonia into: 5-nitro-3-{N-(1,3,4-
trihydroxy-threo-but-2-yl~}carbamoy:L benzamide (4)
The ester (3, 10.0 g, 0.0305 moles) was
dissolved in methanol (50 ml) and concentrated ammonium
hydroxide (20 ml, ca. 0.3 moles) was added. The
suspension was heated in a sealed vessel at 50-60°C for
30 min when TLC indicated reaction completion. The
methanol and ammonium hydroxide were removed by
distillation, and were replaced by H20 (50 ml). The
mixture was cooled overnight, after which the insoluble
product was filtered, and washed with cold water (5 ml
x 2). Vacuum drying gave the white mixed amide (4,
7.15 g, 75% yield).
E%AKPLS 4
Chlorination of 5-nitroisophthalic acid,
monomethyl ester (1) with thionyl chloride
into: 5-nitroiso~hthalic acid,
monomethyl ester, monoacid chloride (5)
'The title compound (1, 225 g, 1 mole) was
dissolved in ethyl acetate (0.5 L) and N,N-dioethyl-
formamide (0.1 ml) added as a catalyst. The solution
was heated to 70°C and thionyl chloride (219 al, 3
moles) added over 1.25 hr. The temperature was
subsequently maintained at 70°C for 2 hr.
The thionyl chloride was codistilled with
ethyl acetate (200 ml x 3) and the product dissolved in
hot ethyl acetate (250 ml) and precipitated with
cyclohexane (1 L), filtered, and washed with
cyclohexane (200 ml x 2). Drying at 50°C under vacuum
gave a white solid (5, 216g, 89% yield).
~~?~~~..~~
16
EXA~'LE 5
Amidation of 5-nitroisophthalic acid, monomethyl
ester mono acid chloride (5) with aminodioxepan
into: methyl 5-vitro-3-{N-(trans--2,2-dimethyl-6
hydroxy-1,3-dioxepan-5-yl)}carbamoyl benzoate (6)
The monoester, monoehloride (5. 100 g, 0.411
moles) was dissolved in dry tetrahydrofuran (1 L) and
the solid aminodioxepan (132.8 g, 0.825 moles) was
added in portions over 15 min, keeping the temperature
below 25°C with the aid of an ice bath. Thereafter,
the heterogenous mixture was allowed to stir for 30 min
at room temperature, when TLC showed reaction
completion.
The insoluble amine hydrochloride was filtered
off and the tetrahydrofuran was removed from the
filtrate by distillation. The residue was dissolved in
ethyl acetate (400 ml) near the boiling point, and the
solution allowed to stand for several days until
crystallization of the product was complete. The solid
was filtered off, washed with cold ethyl acetate (50 ml
x 2) and dried in a vacuum oven, giving an off-white
product (6, 82.4 g, 55~ yield).
ERAlSPLE 6
Amidation of methyl 5-vitro-3-{N-(traps-2r2-
dimethyl-6-hydroxy-1,3-dioxepan-5-yl)}-
carbamoyl benzoate (6) with ammonium hydroxide
into: 5-vitro-3-{N-(traps-2,2-dimethyl-6-
_~~~droxy-1,3-dioxepan-5-yl)}carbamoyl benzamide (7)
A Parr pressure reactor (800 ml) was charged
with the title compound (6, 80 g, 0.22 moles), methanol
(110 ml) and 15 N ammonium hydroxide (225 ml, 3.38
moles). The reaction vessel was sealed and submerged
in a water bath at 50°C for 2 hr, when TLC indicated
complete reaction. The heterogeneous reaction mixture
was mixed with H20 (100 ml) and then stripped to a
foam. The foam was slurried in H20 (100 ml), filtered
~~~~~3~
17
and washed two times with 50 ml H20 to obtain a white
solid (7, 60.4 g, 79% yield).
E~4PLE 7
Reduction and deprotection of 5-~nitro-3-{N-
(traps-2,2-dimethyl-6-hydroxy-1,3-dioxepan-
5-yl)}carbamoyl benzamide (7) with hydrogen and
palladium on carbon and hydrochloric acid into:
5-amino-(hydrochloride)-3-{N-(1,3,4-trihydroxy-
threo-but-2-yl)}carbamoyl benzamide (8)
A Parr pressure reactor (2.0 L) was charged
with the title compound (7, 58 g, 0.16 moles). 1 N
hydrochloric acid (410 ml) and palladium-on-carbon (10%
Pd/C, 5.8 g, 1% Pd w/w). The reaction vessel was
connected to a hydrogenator and shaken under 50 psi
hydrogen gas for 2 hr, when HPLC indicated 90%
conversion to product (8). The palladium catalyst was
filtered and the acetone formed during deprotection was
removed in vacuo at 50°C. The resulting clear solution
(8, 450 ml, 90% yield) was taken directly to
iodination.
EZAI~PLE 8
Iodination of 5-amino-(hydrochloride)-3-{N
(1,3,4-trihydroxy-threo-but-2-yl)}carbamoyl
benzamide (8) with iodine monochloride into:
5-amino-2,4,6-triiodo-3-{N-(1,3,4-trihydroxy
_threo-but-2-yl)}carbamoyl benzamide (9)
The title compound (8, 0.14 moles) in 1 N
hydrochloric acid (450 ml) was heated to 85°C and
iodine monochloride (135 ml, 0.49 moles) was added.
The reaction mixture was heated at 85°C for 2 hr, when
HPLC indicated that the reaction was done. The
reaction mixture was cooled to 25°C and extracted 2 x
cyclohexene (200 ml), 3 x dichloromethane (300 ml), and
5 x chloroform (200 ml) until all the purple color was
removed from the aqueous layer. The resulting light
18
yellow solution was recirculated on a column containing
Duolite-A340 (800 g) and Dowex 50W-X8 (266 g) resins.
The resins were flushed with H20 (6 L) and the solution
was concentrated to 300 ml when a white crystalline
solid began crystallizing. The product was filtered to
obtain a white solid (9, 40 g, 0.06 moles, 43% yield).
EXAMPLE 9
Acetylation of 5-amino-2,4,6-triiodo-3-{N
(1,3,4-trihydroxy-threo-but-2-yl)}carbamoyl
benzamide (9) with acetic anhydride into:
5-diacetylamino-2,4,6-triiodo-3-{N-(1,3,4-
triacetoxy-threo-but-2-yl)}carbamoyl benzamide (10)
The title compound (9, 90 g, 0.14 moles) was
mixed with acetic anhydride (500 ml, 4.95 moles) at
70°C, with vigorous stirring. Perchloric acid (0.36
ml, 0.004 moles) catalyst was added, causing the
temperature to rise to 85°C. The reaction mixture was
stirred at 85°C for 1 hz, when it became homogenous and
TLC indicated reaction completion. Sodium acetate
(0.33 g, 0.004 moles) was added to neutralize the
perchloric acid, and the solvent was removed to obtain
a thick brown oil. The oil was diluted with butyl
acetate (200 ml) at 70°C, followed by solvent
removal. The stripping procedure was repeated two
times to obtain a brown foam (10, 113 g, 0.13 moles,
93% yield).
E%A~1PLE 10
Deacetylation and alkylation of 5-diacetylamino-
2,4,6-triiodo-3{N-(1,3,4-triacetoxy-threo-but-
2-yl)}carbamoyl benzamide (10) with sodium
methoxide and 2-chloroethanol into: 5- N-
(2-hydroxyethylacetamido)}-2,4,6-triiodo-3-
(N-(1,3,4-trihydroxy-threo-but-
2-yl)}carbamoyl benzamide (11)
The title compound (10, 113 g, 0.13 moles) was
19
dissolved in methanol (500m1) to whit:h was added 25~
sodium methoxide (55 g, 0.25 moles) at 50°C. After 5
hr, HPLC indicated the deacetylation was complete and
the solution was neutralized with Dowex 50 W-X4 resin
(10 g). The resin was filtered and the filtrate was
concentrated to 400 ml. The neutral methanolic
solution was warmed to 45°C and charged with trisodium
phosphate dodecahydrate (129 g, 0.34 moles) and 2-
chloroethanol (18.2 ml, 0.272 moles). The reaction was
stirred at 45°C for 48 hr, when chloroethanol (4.7 ml,
0.07 moles) and sodium methoxide (14.7 g, 0.07 moles)
was added. After 71 hr, HPLC indicated the reaction
had gone to completion. The insoluble salts (89 g)
were removed by filtration and the solution neutralized
with hydroxhloric acid (6 N, 7 ml). The solution was
concentrated to obtain a brown foam (11) (94 g, 0.12
moles, 92~ yield).
E~AI~LB 11
Amidation of 5-nitroisophthalic acid,
monomethyl ester (1) with 3-amino-
1,2-propanediol into: 5-vitro-3-(N-(2,3-
dihydroxypropyl)}carbamoyl benzoic acid (12)
The starting material (1, 225 g, 1 mole) was
mixed with 3-amino-1,2-propanediol (227.8 g, 2.5 moles)
and the heterogeneous mixture was heated to 110-120°C
for 1 hr. At this point, the reaction was complete,
and the homogeneous mixture was mixed with water (1 L),
and concentrated HC1 (170 ml). The mixture was cooled
for several days to fully precipitate the product, and
the solid was filtered off and washed with cold water
(50 ml x 2). Vacuum drying gave a white solid (12, 193
g, 68~ yield).
20
ExP~9PLE 12
Reduction of 5-nitro-3-{N-(2,3-dihydroxy
propyl)}carbamoyl benzoic acid (12)
with hydrogen and palladium-on-carbon
into: 5-amino-(hydrochloride)-3-{N-(2,3-
dihydroxypropyl)}carbamoyl benzoic acid (13~
The vitro acid (12, 180 g, 0.634 moles) was
mixed with water (1 L), and concentrated HCl (60 ml)
and 10% palladium-on-carbon (18 g) were added. The
suspension was hydrogenated at 2-4 atmospheres until
the pressure remained constant, by which time HPLC and
TLC indicated reaction completion. The palladium-on-
carbon was removed by filtration and the homogeneous
solution was used without product isolation for the
following reaction (13, approximate yield 98%).
EgAMPLE 13
Iodination of 5-amino-(hydrochloride)-3-{N
(2,3-dihydroxypropyl)}carbamoyl benzoic acid
(13) with iodine monochloride into: 5-amino
2,4,6-triiodo-3-{N-(2,3-dihydroxy-
propyl)}carbamoyl benzoic acid (14)
The title compound (13, ca. 0.62 moles in 1.5
L water) was further diluted with water to a total
volume of 4 L and heated to 85°C. Over 20 minutes,
iodine monochloride (4.1 molar, 499 ml, 2.05 moles) was
added and the temperature maintained at 90°C for 6-8
hr. HPLC indicated reaction completion. The
homogeneous mixture was cooled, extracted with 1,2-
dichloroethane:cycloheYene (9:1, 500 ml x 1), followed
by 1,2-dichloroethane (250 ml x 2). The aqueous layer
was then concentrated by distillation to 0.9 L, and
cooled for several days to complete the precipitation
of the solid. Filtration, washing with cold water (100
ml x 2) and vacuum drying gave the tan product (14, 286
g, 73% yield).
21
EXAMPLE 14
Acetylation of 5-amino-2,4,6-triiodo-3
{N-(2,3-dihydroxypropyl)}carbamoyl benzoic
acid (14) with acetic anhydride into:
5-diacetylamino-2,4,6-triiodo-3-{N-
(2,3-diacetoxypropyl)}carbamoyl benzoic acid (15)
The starting material (14, 100 g, 0.158 moles)
was mixed with acetic anhydride (300 ml, 3.16 moles)
and 70% perchloric acid (0.2 ml), and heated to BO-90°C
for 8 hr. The mixture was neutralized with anhydrous
sodium acetate (0.25 g) and the acetic anhydride and
acetic acid removed by distillation at 70-80°C. The
oily residue was azeotroped with butyl acetate (100 ml
x 2), then dissolved in ethyl acetate (250 ml), and
taken directly into chlorination (15, approximate yield
90%).
EXAMPLE 15
Chlorination of 5-diacetylamino-2,4,6-
triiodo-3-{N-(2,3-diacetozypropyl)}-
carbamoyl benzoic acid (15) with thionyl
chloride into: 5-diacetylamino-2,4,6-trifodo
-3-{N-(2,3-diacetoxypropyl)}carbamoyl
benzoyl chloride (16)
To the starting material (15, ca. 0.142 moles)
in ethyl acetate (225 ml) was added thionyl chloride
(5? ml, 0.78 moles) at 65-70°C, and the temperature
increased afterwards to ?5-80°C for 1 hr. Thionyl
chloride and ethyl acetate were vacuum distilled. The
residue was azeotroped with butyl acetate (100 ml z 2),
and vacuum dried. The brown foam (16, ca. 130 g,
estimated yield 95%) was taken directly into the
subsequent amidation step.
22
ALE 16
Amidation of S-diacetylamino-2,4,6-triiodo
3-(N-(2,3-diacetoxypropyl)}carbamoyl benzoyl
chloride ( _16) with ammonia into: S-acetylamino
2,4,6-triiodo-3-{N-(2,3-diacet_oxy-
propyl)}carbamoyl benzamide (17)
The acid chloride (16, ca. 0.135 moles), was
dissolved in dry N,N-dimethylacetamide (150 ml). This
solution was cooled to 0-5°C, anhydrous ammonia (ca. 20
ml) was condensed into the mixture using a dry
ice/acetone condenser and the reaction mixture was kept
sealed at room temperature for 24 hr. The ammonia and
DMA were removed by vacuum distillation. 1-pentanol
(S00 ml) precipitated a solid which was filtered and
washed with 1-pentanol (150 ml x 2). Vacuum drying
gave a tan solid (17, 82 g, 80.2; yield).
B~L$ 17
Deacetylation of 5-acetylamino-2,4,6
triiodo-3-{N-(2,3-diacetoxypropyl)}carbamoyl
benzamide (17) into: 5-acetylamino-2,4,6-
triiodo-3-{N-(2,3-dihydroxypropyl)}
carbamoyl benzamide (18)
The title compound (17, 81.2 g, 0.107 moles)
was suspended in water (203 ml) and then treated with
the dropwise addition of 50t w/w sodium hydroxide in
water (16.9 ml, 0.322 moles). With stirring, total
solution was obtained. The solution was degassed under
vacuum for 30 min at which time 12 M HCl (15 ml, 0.18
moles) was added. After storage at 4°C, the resulting
precipitated solid was filtered, washed with ice water
(3 x 50 ml), ethanol (80 ml), and vacuum dried to the
product (18, 54.1 g, 75~ yield).
~~~~~~9
23
EXAMPLE 18
Alkylation of 5-acetylamino-2,4,ti-triiodo-3
{N-(2,3-dihydroxypropyl)}carbamoyl benzamide
(18) into: 5-{N-(2,3-dihydroxypropyl)
acetamido}-2,4,6-triiodo-3-{N-(2,3-
dihydroxypropyl)}carbamoyl benzamide (19)
The title compound (18), 39.7 g, 0.059 moles)
was dissolved in propylene glycol (16.7 ml), ethanol
(120 ml), and 25~ w/w sodium methoxide (17.6 ml, 0.077
moles). Chloropropanediol (9.78 g, 0.0885 moles) was
added and the mixture was stirred at 25°C for 1 hr.
The reaction was warmed to 33°C and stirred for another
19 hr during which time 25% w/w sodium methoxide (3.4
ml, 0.015 moles) was added. The reaction was quenched
with 12 M HC1, distilled under vacuum, reconstituted
with H20 (200 ml), and disttilled again to give an
aqueous solution that was deionized with Dowex 50 H+
resin (62 g) and Duolite A-340 OH- resin (140 g).
Elution of the resins with H20 and concentration gave a
150 g solution that was treated with Norit Ultra S%
charcoal (1.00 g) at 60°C for 14 hr. The charcoal was
filtered giving an aqueous solution that was stirred
for 2 hr with Dowex 50 H+ (1.0 g) and Duolite A-340 OH
(4 g). The resin was filtered and the aqueous solution
was distilled to 50.3 g of an oil containing the
product (19, 32.8 g, 74% yield) in a glycerol/propylene
glycol base. This oil was purified as described in the
following step.
EgA~PLB 19
Peracetylation, silica column purification,
and subsequent deacetylation of: 5- N-
(2,3-dihydroxypropyl)acetamido}-2,4,6-
triiodo-3-{N-(2,3-dihydrox ro yl)}
carbamoyl benzamide (19)
The title compound (19, 16.4 g, 0.022 moles)
dissolved in glycerol/propylene glycol oil (total mass,
24
25.15 g) was diluted with pyridine (1.74 g, 0.022
moles) and acetic anhydride (115 g, 1.,12 moles), and
then warmed to 60°C for 18 hr. The reaction was
distilled under reduced pressure to an oil, dissolved
in CHC13 (100 ml) and extracted with 0.1 N HC1 (2 x 50
ml) and 15% w/v brine (2 x 50 ml). The CHC13 layer was
dried over MgS04, filtered, and distilled to an oil.
This oil was purified on a 900 g silica column
utilizing a solvent gradient which ran from 5% acetic
acid, 95% chloroform to 5% acetic acid, 4% methanol,
91% chloroform. Purified fractions were combined,
distilled to a foam, and then treated with methanol (30
ml) and 25% w/w sodium methoxide in methanol (0.98 g,
0.0054 moles). After 30 min, the solution was
distilled, reconstituted with methanol (20 ml), and
then stirred with Dowex 50 H+ resin (1.3 g). After the
pH decreased from 12 to 5, the resin was filtered off,
giving a solution that was distilled to a foam,
reconstituted with H20 (25 ml), and evaporated to the
solid title compound (19, 8.12 g, 49% yield).
EBANPLB 20
Deacetylation of 5-diacetylamino-2,4,6-
triiodo-3-{N-(2,3-diacetoxypropyl)}carbamoyl-
benzoic acid (15) into: 5-acetylamino
2,4,6-triiodo-3 ~ N-(2,3-dihydroxypropyl)}
carbamoyl benzoic acid (20)
The title compound (15, 720 g, 0.9 moles) was
dissolved in 500 ml methanol, and 25% w/w sodium
methoxide in methanol (345 ml, 1.5 moles) was added.
After 4 hr at 45-50°C the reaction was distilled under
reduced pressure, acidified with 12 M HC1 (124 ml, 1.5
moles), and the salts filtered off. The filtrate was
distilled under reduced pressure to give an oil which
was diluted with n-propanol (680 ml). After
crystallizing at 4°C, the resulting solid product (20)
was filtered off, washed with n-propanol (2 x 300 ml),
?Q~~~j~
z5
and dried in vacuo. Yield was 391 g (64%).
~xAMPL~ 21
Alkylation of 5-acetylamino-2,4,6-triiodo
-3-{N-(2,3-dihydroxypropyl)}carbamoyl benzoic
acid (20) into: 5-{N-(2,3-dihydroxypropyl)
acetamido}-2,4,6-triiodo-3-{N-)2,3-
dihydroxypropyl)}carbamoyl benzoic
_acid, sodium salt (21)
The title compound (20, 100 g, 0.148 moles)
was dissolved in 400 ml methanol. Solid Na3P04~12 H20
(140.6 g, 0.37 moles) was added, followed by
chloropropanediol (32.7 g, 0.296 moles) and 25% w/w
sodium methoxide in methanol (24.1 g, 0.111 moles),
added dropwise. The reaction mixture was warmed to
40°C for 10 hr during which more 25% sodium methoxide
(8.0 g, 0.0368 moles) was added in portions. Salts
were filtered off and the methanol filtrate was
acidified with 12 M HC1 (3.5 ml), rotavaped to a thick
oily product (21) and carried directly into the next
reaction.
.s 2z
Acetylation of the sodium salt of 5-{N-(2,3-
dihydroxypropyl)acetamido}-2,4,6-triiodo-
3-{N-(2,3-dihydroxypropyl)}carbamoyl benzoic
acid (21) into: 5-{N-(2,3-diacetoxypropyl)
acetamido}-2,4,6-triiodo-3-{N-(2,3-
d_iacetoxypropyl)}carbamoyl benzoic acid (22)
The title compound (21, 114 g. 0.148 moles)
oil, was diluted with pyridine (11.7 g, 0.148 moles)
and acetic anhydride (605 g, 5.92 moles) and stirred at
65-70°C for 2 hr. The reaction was distilled to an
oil, azeotroped with butyl acetate (2 x 100 ml), and
partitioned between water (300 ml) and 3:1
toluene:ethyl acetate (200 ml). The water layer was
extracted with 3:1 toluene:ethyl acetate (3 x 100 ml)
26
and acidified with HC1 (22.5 ml) in the presence of
ethyl acetate (300 ml). The acidified H20 layer was
separated and extracted twice with ethyl acetate (100
ml). The three latter ethyl acetate extracts were
combined, dried over MgS04, filtered. and evaporated to
a solid product (22, 118 g, 87% yield).
EXAMPLE 23
Chlorination of 5-{N-(2,3-diacetoxypropyl)-
acetamido}-2,4,6-triiodo-3-{N-(2,3-diacetoxy-
propyl)}carbamoyl benzoic acid (22) into:
5-{N-(2,3-diacetoxypropyl)acetamido}-2,4,6
triiodo-3-{N-(2,3-diacetoxypropyl)}
carbamoyl benzoyl chloride (23)
The title compound (22, 113.6 g, 0.124 moles)
was dissolved in ethyl acetate (100 ml) at 55°C;
thionyl chloride (44 g, 0.37 moles) was added dropwise
and the mixture was refluxed for 2 hr, rotavaped to an
oil, and then azeotroped with butyl acetate (2 x 50 ml)
to give a foam which was dissolved in chloroform (200
ml) and extracted with 0.2 M pH 6.7 phosphate buffer
(100 ml). The organic layer was dried over MgS04,
filtered, and evaporated to a solid product (23, 115 g,
98% yield).
EBAMPL$ 24
Amidation of 5-{N-(2,3-diacetoxypropyl)-
acetamido}-2,4,6-triiodo-3-{N-(2,3-
diacetoxypropyl)}carbamoyl benzoyl
chloride (23) into: 5-{N-(2,3-diacetoxy-
~ro~yl)acetamido}-2,4,6-triiodo-3-{N-(2,3-
_diacetoxypropyl)}carbamoyl benzamide (24)
The title compound (23, 105 g, 0.111 moles)
was dissolved in acetonitrile (400 ml) to which
anhydrous ammonia was added by utilizing a dry ice
condenser at 25°C. After 3 hr of NH3 reflux, the
reaction was complete. Salts were filtered off, and
27
evaporation yielded a solid product (24, 98.8 g, 96%
yield).
EXAlIPLE 25
S Deacetylation of 5-{N-(2,3-diacetoxypropyl)
acetamido}-2,4,6-triiodo-3-{N-(2,3-
diacetoxypropyl)}carbamoyl benzamide (24)
into: 5-{N-X2,3-dihydroxypropyl)acetamido}
-2,4,6-triiodo-3-{N ,2,3-dihydroxypropyl)}
carbamoyl benzamide (19)
The title compound (24, 98.7 g, 0.106 moles)
was dissolved in methanol (250 ml) to which 25% w/w
sodium methoxide in methanol (2.30 g, 0.0106 moles) was
added at 25°C. After 15 min, the solution was
distilled under vacuum to an oil, reconstituted with
methanol (200 ml) and then stirred with Dowex 50 H+
resin (6.0 g) until the pH decreased from 12 to 6. The
resin was filtered off to produce a solution that was
distilled to a foam, reconstituted With water (320 ml)
and Norit SX charcoal (3.0 g), reflwced for 7 hr,
filtered, deionized by stirring with DoweY 50 H+ resin
(3 g) and Dowex XUS-40123 OH- resin (12 g), filtered,
and evaporated to the solid product (19, 79.2 g, 96%
yield).
EXAHPLB 26
Methoxyacetylation of 5-amino-2,4,6-triiodo
-3-{N-(1,3,4-trihydroxy-threo-but-2-yl)}
carbamoyl benzamide (9) with methoxyacetyl
chloride into: 5-methoxyacetylamino-2,4,6
triiodo-3-{N- X1,3,4-trihydroxy-threo
but-2-yl)}carbamoyl benzamide (25)
The title compound (9, 100 g, 0.15 moles) was
suspended in N,N-dimethylacetamide (250 ml) at 25°C to
which was added methoxyacetyl chloride (68 ml, 0.75
moles) over 30 min. The reaction mixture was stirred
at 35°C for 5 hr, when HPLC indicated that the reaction
~~~~a~:
z8
was complete. The reaction mixture was quenched with
sodium methoxide (97 g, 0.45 moles) and the mixture was
stirred at 40°C Eor 2 hr. The solution was neutralized
with Dowex 50W-X4 resin, filtered and diluted with
n-butanol (700 ml). A white precipitate formed
immediately and was filtered to obtain an off-white
solid (25, 80.6 g, 0.11 moles, 73% yield).
EXAMPLE 27
Alkylation of Ioxithalamic Acid (26) to:
5-{N-(2,3-dihydroxypropyl)acetamido}-2,4,6-triiodo-
3-{N-(2-hydroxyethyl)}carbamoyl sodium benzoate (27)
Ioxithalamic acid (26, 966 g, 1.5 moles) was
dissolved in 1 N sodium hydroxide (1.5 L) at room
temperature, warmed to 75°C, and 3-chloro-1,2-propan-
ediol (223.8 g, 2.03 moles) and 5 N sodium hydroxide
(approximately 0.4 L) were added simultaneously over
1.25 hours. The reaction was heated at 80-90°C for a
further 2.5 hours, at which point HPLC showed
completion of the reaction (ca. 90% conversion to
product).
The reaction mixture was neutralized with
concentrated hydrochloric acid (ca. 3 ml) and
evaporated. About half of the foamy residue was taken
up in water (0.4 L). On cooling, a white, crystalline
solid precipitated, which was filtered and washed with
ice cold water. Drying gave the crystalline product
(27, 249 g).
S~AMpLE 28
Acetylation of 5-{N-(2,3-dihydroxypropyl)
acetamido}-2,4,6-triiodo-3-{N-(2-hydroxyethyl)}
carbamoyl-sodium benzoate (27) to:
5-{N-(2,3-diacetoxy ropyl)acetamido}-2,4,6-triiodo-
3-{N-(2-acetoxyethyl)}carbamoyl-benzoic acid (28)
The title compound (27), 50 g, 0.067 moles)
was added to stirred acetic anhydride (102 ml, 1.080
~~~~4~9
29
moles, 16.0 eq.) at 25°C Pyridine (5.4 ml, 0.067 moles,
1.0 eq.) was added and the temperatures was raised to
85°C for 1 hour when TLC indicated the' reaction had
gone to completion. The homogeneous reaction mixture
was evaporated in vacuo to a thick oil, dissolved in
butyl acetate (50 ml) and repeatedly evaporated. The
oil was dissolved in H20 (260 ml) and extracted with
toluene: ethyl acetate (2:1; 4 x 100 ml). The aqueous
layer was acidified with 12 N hydrochloric acid (11 ml)
and extracted with ethyl acetate (3 x 50 ml). The
organic layer was dried over magnesium sulfate,
evaporated to a foam (28) and taken directly to the
next step (55 g, 0.065 moles, 97% yield).
ERAMPLE 29
Chlorination of 5-{N-(2,3-diacetoxypropyl)
acetamido}-2,4,6-triiodo-3-{N-(2-acetoxy
ethyl)}carbamoyl-benzoic acid (28) to:
5-~N-(2,3-diacetoxypropyl)acetamido}-2,4,6-triiado-3-
{N-(2-acetoxyethyl)}carbamo~l-benzoyl chloride (29)
The title compound (28, 55 g, 0.065 moles) was
dissolved in 1,2-dichloroethane (170 ml) and heated to
85°C. Thionyl chloride (9.8 ml, 0.134 moles, 2.0 eq.)
was added and TLC indicated the reaction had reached
completion after 3 hours. The reaction mixture was
evaporated in vacuo to an oil, redissolved in butyl
acetate (50 ml) and repeatedly evaporated. The product
was isolated as a yellow foam (29), 51.9 g, 0.060
moles, 92% yield).
EXAI~PLS 30
Amidation of 5-{N-(2,3-diacetoxypropyl)
acetamido}-2,4,6-triiodo-3-{N-(2-acetoxyethyl)}
carbamoyl-benzoyl chloride (29) to:
5-{N-(2,3-diacetoxypcopyl)acetamido}-2,4,6-triiodo-
. 3-~N-(2-acetoxvethyl)}carbamoyl-benzamide (30)
The title compound (29, 51.9 g, 0.060 moles)
x
was dissolved in acetonitrile (200 ml) and anhydrous
ammonia (excess) was added at 10°C. After 4 hours, TLC
indicated the reaction was complete. The reaction
mixture was filtered to remove ammonium chloride salts
5 and the solvent was removed to give a yellow oil (30,
47 g, 0.056 moles, 93% yield).
ERAMPLE 31
Deacetylation of 5-{N-(2,3-diacetoxypropyl)
10 acetamido}-2,4,6-triiodo-3-{N-(2-acetoxy
ethyl)}carbamoyl-benzamide (30) to:
5-{N-(2,3-dihydroxypropylacetamido)}-2,4,6-triiodo
3-{N-(2-hydroxyethyl)}carbamoyl-benzamide (31)
The title compound (30, 47 g, 0.056 moles) was
15 dissolved in methanol (240 ml) and 25% sodium methoxide
(3.9 g, 0.3 eq.) was added to raise the pH to ca. 12.
The solution was stirred at 25°C for 1 hour when HPLC
indicated the deacetylation was complete. The reaction
mixture was neutralized with 1 N HC1 (10 ml) and
20 solvent removal gave an off-white foam (31, 39 g, 0.054
moles, 97% yield, 98% pure), which was recrystallized
from hot methanol (5 g in 15 ml, with seeding).
E%AlsPLE 32
25 Amidation of 5-amino-2,4,6-triiodo-
isophthaloyl chloride (32) into:
_5-amino-2,4,6-triiodo-3-chlorocarbonyl-benzamide (33)
The starting material (32, 300 g, 0.503 moles)
was dissolved in tetrahydrofuran (900 ml) and the
30 homogeneous solution cooled in ice to 5-10°C.
Concentrated ammonium hydroxide (92.3 ml, 1.38 moles)
was added over 10 minutes; the temperature rose to
30°C.
The reaction mixture was stirred at room
temperature for a total of 90 hours, with further
additions of ammonium hydroxide (total 25.2 ml, 0.38
moles), then it was cooled and the insoluble salts
31
removed by filtration. The filtrate was washed with
saturated NaCl (a00 ml x 2).
The tetrahydrofuran was evaporated to give a
viscous oil. Ethyl acetate (800 ml) precipitated a tan
solid which was filtered, washed with ethyl acetate
(100 ml x 2) and dried to give (33, 153 g, 66.5%
yield).
EXAMPLE 33
Dimerization of 5-amino-2,4,6-triiodo-3-
chlorocarbonyl-benzamide (33) into:
Malonic Acid-bis-{(3-chlorocarbonyl-5-
carbamoyl)-2,4,6-triidodanilide} (34)
The title compound (33, 20.0 g, 34.7 mM) was
dissolved in dzy tetrahydrofuran (100 ml), heated to
45°C, and malonyl dichloride (2.53 ml, 26 mM) was added
over 3 minutes to give a heterogeneous mixture. Dry
THF (100 ml) was added, and the suspension stirred~for
1 hour when TLC showed the reaction to be complete.
The mixture was diluted with butyl acetate (150 ml),
and the solid was filtered, washed with butyl acetate
(50 ml x 2) and dried in vacuo to give the product (34,
13.18 g, 62% yield).
2 5 ExAbIPLg 34
Amidation of Malonic Acid-bis-{(3-chlorocarbonyl
S-carbamoyl)-2,4,6-triiodoanilide} (34) into:
Malonic Acid-bis-({3-N-(1,3,4-trihydroxy-threo-but-2
yl-carbamoyl-5-carbamoyl}-2,4,6-triiodoanilide] (35)
The title compound (34, 8.0 g, 6.56 mM) was
dissolved in dry N,N-dimethyl-acetamide (10 ml),
triethylamine (1.83 ml, 13.12 mM) was added and the
solution was cooled to 20°C. Traps-S-amino-2,2-
dimethyl-6-hydroxy-1,3-dioxepan (2.64g, 16.4 mM) was
added over 3 minutes, and the homogeneous mixture was
stirred at room temperature for 6 hours, when TLC
indicated the reaction was complete. The solvent was
32
evaporated, water (50 ml) was added, and the mixture
was heated at 75°C for 15 minutes to cleave the
acetonides. The product was obtained by evaporation
and precipitation with isopropanol (7.00 ml). The solid
was filtered, washed with isopropanol. (20 ml x 2) and
dried to give 8.6 g (35, 94% yield).
EXAMPLE 35
Amidation of 5-N-methylamino-2,4,6-triiodo-
isophthaloyl-chloride (36) to:
5-N-methylamino-2,4,6-triiodo-3-
chlorocarbonyl-benzamide (37)
The starting material (36, 305 g, 0.5 moles)
was dissolved in tetrahydrofuran (1 L) and cooled to
10°C. Concentrated ammonium hydroxide (100 ml, 1.5
moles) was added over 5 minutes; the temperature rose
to ca. 25°C.
The reaction mixture was stirred at room
temperature for 65 hours, with additional portions of
concentrated NH40H added at 20 hours (3.5 ml) and 44
hours (3.5 ml).
Upon cooling, the insoluble salts and bis-
amide were filtered and the THF filtrate washed with
saturated sodium chloride solution (100 ml x 2).
The THF was evaporated and the product
precipated from the thick oil by ethyl acetate (500
ml). Filtration, washing with ethyl acetate and drying
gave (37, 132.1 g, 45% yield).
EBAI~PLE 36
Dimerization of 5-N-methylamino-2,4,6-triiodo-
3-chlorocarbonyl-benzamide (37) into:
Malonic Acid-bis-((3-chlorocarbonyl-5-
carbamoYl)-2,4,6-triiodo-N-methyl anilide} (38)
The title compound (37, 25 g, 42.3 mM) was
dissolved in dry tetrahydrofuran (100 ml) and the
homogeneous solution was heated to 50°C. Malonyl
~)~~y~ ~~~(
33
dichloride (3.05 ml, 31.3 mM) was added over 2 minutes,
followed by additional tetrahydrofuran (50 ml) and the
suspension was heated far one hour, when TLC showed the
reaction was complete.
Upon dilution with butyl acetate (50 ml), the
product was filtered, washed with butyl acetate (25 ml
x 2) and dried to give an off-white solid (38, 15.24 g,
58~ yield).
EXAMPLE 37
Transformation of Malonic Acid-bis-{(3-chlorocarbonyl
5-carbamoyl)-2,4,6-triiodo-N-methyl anilide} (38) into:
Malonic Acid-bis-[~3-N-(1,3,4-trihydroxy-threo
but-2-yl-carbamoyl) 5-carbamoyl}-2,4,6-triiodo
N-methyl anilide] (39)
The starting material (38, 10 g, 8 mM) was
dissolved in dry N,N-dimethyl-acetamide (15 ml) and
triethylamine (2.23 ml, 16 mM). Trans-5-amino-2,2-
dimethyl-6-hydroxy-1,3-dioxepan (aatinodioxepan) (3.22
g, 20 mM) was added over S minutes, and the homogeneous
mixture was stirred for 8 hours, when TLC showed the
reaction to be complete.
The DMA was removed by vacuum distillation and
the isopropylidenes were cleaved with aqueous hydro-
chloric acid at 50°C. The water was removed on the
rotary evaporator and isopropanol added to precipitate
the product. Filtration, washing with isopropanol (10
ml x 3), and drying gave the dimer (39, 9.86 g, 87%
yield).
EXAMPLE 38
5-N-(methyl)amino-2,4,6-triiodo-3-
chlorocarbonyl-benzamide (36) into:
5-{N-(methyl)-2-acetoxyacetamido}-2,4,6-
_triiodo-3-chlorocarbonyl-benzamide (40)
The starting material (36, 25 g, 42.3 mM) was
dissolved in dry N,N-dimethyl-acetamide (50 ml) at room
34
temperature. 2-Acetoxyacetyl chloride (6.83 ml, 63.5
mM) was added, and after stirring overnight, TLC
indicated the reaction was complete.
The product was precipitated by the addition
of ice-cold water (200 ml) and filtered. After dashing
with water the solid was dissolved in tetrahydrofuran
(200 ml), and the solution extracted with saturated
NaCl:saturated NaHC03 (3:1, 250 ml), followed by
saturated NaCl (100 ml). The organic layer was dried
(MgS04) and the solvent removed to give a foam (40,
22.1 g, 77.2 yield).
ExAMPLE 39
Amidation and Deprotection of 5-{N-(methyl)-
2-acetoxyacetamido}-2,4,6-triiodo-3-
chlorocarbonyl-benzamide (40) into:
5-~N-(methyl)-2-hydroxyacetamido}-2,4,6-triiodo
3-{N-(1,3,4-trihydroxy-threo-but-2-yl)}
carbamoyl-benzamide (41)
The title compound (40, 7.0 g, 10.35 mM)' was
dissolved in a mixture of tetrahydrofuran (40 ml) and
triethylamine (1.44 mlr 10.35 mM) and cooled to 10°C.
Solid aminodioxepan (2.0 g, 12.41 mM) was added, the
cooling was removed and the reaction was allowed to
stir at 25°C. By 18 hours, TLC indicated reaction
completion. The reaction mixture was diluted with
tetrahydrofuran (40 ml) and saturated NaCl:saturated
NaHC03 (3:1, 50 ml) and the layers were separated. The
organic layer was washed with saturated NaCl (40 ml x
2), dried (MgS04) and the solvent evaporated to give a
foam (6.9 g, 823 yield).
The foam was dissolved in methanol (50 ml) and
4.6 formal NaOMe solution (0.5 ml) added. The solution
was stripped at 50°C to yield an oil which was
subsequently mixed with water (50 ml) and Dowex 50 H~
resin (10 g). Heating at 60°C for 30 minutes
eventually gave a homogeneous solution, and HPLC
~~~Q~~~
indicated that ester and isopropylidene~ cleavage was
complete.
The resin was filtered, and the solution
cycled through sequential Duolite A 340 OH-/Dowex SO H+
5 columns until deionization was completE~. The compound
was eluted from the columns with water and subsequently
treated with Norit Ultra S-X carbon (0.4 g). After 1
hour at 70°C, the carbon was filtered and the water
evaporated to yield a white foam (41, 3.8 g, 50~ yield
10 from 40).
20
30
EXAMPLE 40
Acetoxyacetylation of 5-amino-2,4,6-triiodo-3-chlorocarbonyl
benzamide (33) unto 5-acetoxyacetylamino-2,4,6-triiodo-3-
chlorocarbonyl benzamide (42)
The starting material (33, 200 g, 0.347 moles) in 1200 ml dioxane
was heated to 60oC. Acetoxyacetyl chloride (142 g, 1.041 moles)
was added dropwise over 15 minutes at which time the reaction was
heated to 90oC and held there for 6.5 hours. After cooling to
lSoC the solid product (42) was filtered, washed with 4 x 100 ml
ZO dioxane and vacuum dried to a weight of 200.5 g (yield 85~).
EXAMPLE 41
Amidation of 5-acetoxyacetylamino-2,4,6-triiodo-3-chlorocarbonyl
benzamide (42) into 5-acetoxyacetylamino-2,4,6-triiodo-3-{N-(2,3-
dihydroxypropyl)}-carbamoyl benzamide (43)
The starting material (42, 118 g, 0.174 moles) was added to a
flask containing N,N-dimethyl acetamide (180 ml), 3-amino-1,2-
propanediol (24.2 g, 0.266 moles) and triethylamine (18.0 g,
0.177 moles). The reaction was held at 25°C for 4 hours and was
then diluted by the dropwise addition of n-pentanol (1080 m1)
during vigorous mechanical stirring. The resulting precipitate
(43) was filtered, washed with 4 x 100 ml n-pentanol, and vacuum
dried to a weight of 124.9 g (crude yield 98~).
EXAMPLE 42
Deacetylation of 5-acetoxyacetylamino-2,4,6-triiodo-3-{N-(2,3-
dihyroxypropyl)}-carbamoyl benzamide (43) into 5-
hydroxyacetylamino-2,4,6-triiodo-3-{N-(2,3-dihydroxypropyl)}-
carbamoyl benzamide (44)
- 35a -
The starting material (43, 124.8 g, 0.170 moles) was dissolved in
methanol (1.5L) and water (0.5L) and then treated with Dowex 50
H+ and Biorex 5 OH ion exchange resins. The resins were removed
with a sieve after 20 hours of stirring and the resulting mixture
was distilled under reduced pressure to a solid residue.
Methanol (400 ml) and 25~ w/w sodium methoxide in methanol (36.9
g, 0.17 moles) were added to the residue to produce a solution
which was filtered, distilled under pressure to remove methyl
acetate, diluted with methanol, neutralized with concentrated HC1
and then distilled under reduced pressure to a solid consisting
of 9.9 g NaCl and 94.0 g of the product (44). The yield was 80~.
EXAMPLE 43
Protection of 5-hydroxyacetylamino-2,4,6-triiodo-3-{N-(2,3-
dihydroxypropyl)}-carbamoyl benzamide (44) with 3,4-dihydro-2H-
pyran into 5-(2-tetrahydropyranyloxy)acetylamino-2,4,6-triiodo-3
{N-(2,3-tetrahydropyranyloxy)propyl}carbamoyl benzamide (45)
The starting material (44, 3.44 g, 5mmoles) was mixed with
dioxane (15 ml) and methanesulfonic acid (29.6 mg = 0.31 mmoles).
3,4-Dihydro-2Hpyran (3.36 g, 40 mmole) was added and the mixture
was stirred at 25°C for 4 days. The reaction was filtered,
basified with triethylamine (62 mg, 0.62 mmole), distilled under
reduced pressure to an oil, reconstituted with methanol, and
distilled under reduced pressure to a product residue (45) which
was carried directly into alkylation.
EXAMPLE 44
Alkylation and Deprotection of 5-(2-
terthydropyranyloxy)acetylamino-2,4,6-triiodo-3-{N-(2,3-
tetrahydropyranyloxy)propyl}carbamoyl benzamide (45) into 5-{N-
(2-hydroxyethyl)hydroxyacetamido}-2,4,6-triiodo-3-{N-(2,3-
dihydroxypropyl)}carbamoyl benzamide (46)
- 35b -
The starting material (45, 50. mmole). a semisolid residue from
the previous step, was mixed with methanol (18 ml), trisodium
phosphate dodecahydrate (4.75 g, 12,.5 mmoles) and chloroethanol
(805 mg, 10 mmoles). The resulting suspension was stirred at 40-
45oC for 31 hours, filtered and diluted with 0.5 ml concentrated
HC1. The acidified filtrate was distilled under reduced pressure
to an oil and reconstituted with 0.01 N HCl (20 ml) and methanol
(20 ml). After repeating this twice more, the acidic solution
was finally distilled under reduced pressure to solid product
(46) weighing 3.50 g, yield 95~.
EXAMPLE 45
Alkylation of 3,5-diacetylamino-2,4,6-triiodobenzoic acid
(diatrizoic acid, 47) into Sodium 3,5-{N, N'-(2,3-
dihydroxypropyl)diacetamido}-2,4,6-triodobenzoate (48)
To a suspension of the starting material (47, 50 g, 0.079 moles)
in methanol (300 ml) was added trisodium phosphate dodecahydrate
(149 g, 0.393 moles) and 3-chloro-1,2-propanediol (35 g, 0.314
moles) and the reaction was heated at 40°C for 24 hours.
Insoluble salts were removed by vacuum filtration, the filtrate
was neutralized with HC1 and evaporated to a white foam (4~, ca.
59 g, yield 94~ including 10~ ester byproduct). The foam was
taken directly into acetylation.
EXAMPLE 46
Acetylation of Sodium 3,5-{N, N'-(2,3-dihydroxypropyl)
diacetamido}-2,4,6-triiodobenzoata (48) into: 3,5-{N, N'-(2,3-
diacetoxypropyl)diacetamido}-2,4,6-triiodobenzoic acid (49)
The starting material (48, 59 g, 0.075 moles) was mixed with
acetic anhydride (150 ml, 1.58 moles) and pyridine (6 ml, 0.075
moles) and heated to 85oC for 1 hour. The acetic anhydride,
acetic acid and pyridine were removed by distillation at 70-80oC,
- 35c -
and the yellow foam was azet roped with butyl acetate (50 ml x
x2).
The product (sodium salt of 49) was dissolved in water (300 ml)
and extracted with a 2:1 mixture of toluene and ethyl acetate
(150 ml x 3) to remove the ester byproduct from the previous
alkylation step. The aqueous solution was acidified with
concentrated HC1 to pH 2.5 and the white precipitate was
extracted with ethyl acetate (75 ml x 2). The combined organic
extracts were dried over magnesium sulfate and the solvant
removed to give a yellow oil (49, ca. 58 g, 83~ yield overall
from 47). the product was taken directly into chlorination.
EXAMPLE 47
Chlorination of 3,5-{N,N'-(2,3-diacetoxypropyl)diacetamido}-
2,4,6-triiodibenzoic acid (49) into 3,5-{N, N'-(2,3-
diacetoxypropyl)diacetamido-2,4,6-triiodobenzoyl chloride (50)
To the starting material (49, ca. 0.062 moles) in ethyl acetate
(125 ml) was added thionyl chloride (23 ml, 0.32 moles) at 65-
70°C, and the temperature increased to 75-80°C for 1 hour. TLC
indicated that the reaction was complete and thionyl chloride and
ethyl acetate were removed under vacuum. The residue was
azeptroped with butyl acetate (150 ml x 2) and the resultant
solid dried. The tan foam (50, ca. 56 g, yield 95~) was taken
directly into the subsequent amidation step.
EXAMPLE 48
Amidation of 3,5-{N,N'-(2,3-diacetoxypropyl)diacetamido}-2,4,6-
triiodobenzoyl chloride (50) into 3,5-{N, N'-(2,3-
diacetoxypropyl)diacetamido}-2,4,6-triiodo-bensamide (51)
To the starting material (50, ca. 0.059 moles) in acetonitrile
(200 ml) was added anhydrous ammonia (excess) at 10°C, and the
- 35d -
~;~~2~t~n
temperature was increased to 25oC for 5 hours. The reaction was
complete by TLC and the ammonium chloride was removed by
filtration. The filtrate was evaporated to a yellow foam (51, 53
g, estimated yield 97~). The foam was taken directly to
deacetylation.
EXAMPLE 49
Deacetylation of 3,5-{N,N'-(2,3-diacetoxypropyl)diacetamido)-
2,3,6-triiodobenzamidc (51) into 3,5-{N, N'-(2,3-
dihydroxypropyl)diacetamido}-2,4,6-triiodobenzamide (52)
A solution of the starting material (51, ca 0.057 moles) in
methanol (250 ml) was mixed with sodium methoxide (4.6 moles, 5.0
g, 0.023 moles) and was stirred at room temperature for 30
minutes. HPLC showed that the deacetylation was complete and the
reaction mixture was neutralized with concentrated HCl. The
insoluble sodium chloride was removed by filtration and the
filtrate was evaporated to a yellow foam (52, 43 g, yield 97~,
purity 98~ by HPLC).
- 35e -
~~~~J
36
PLE 50
Injection solutions containin
5-{N- 2,3--dih drox-yprop ly )acetamido -2,4,6
-tri~.o 0-3- N-(2,3-di.hydro;K ro 1
carbamoyl enzami'~e (19)
Iodine Content of Injection
Composition of 100 ml Solution in mg/ml
Aliquots of Solution 300 350 400
Compound (g) 58.87 68.68 78.49
Disodium, calcium salt of
ethylenediaminetetraacetic
acid (mg) 10 10 10
Tris-(hydroxymethyl)amino-
methane (mg) 121 121 121
Water for injection to
volume (ml) 100 100 100
Osmolality (mOsm/kg) 399 473 510
Viscosity @ 37C
(centipoise) 4.1 6.6 106
Procedure: The sodium-calcium salt of ethylenediamine-
tetraacetic acid, tris-(hydroxymethyl)aminomethane, and
the contrast media were dissolved in water for
injection and adjusted to pH 7.0 by the addition of 1 N
hydrochloric acid. Solutions were QS'd to 100 ml with
water for injection, filtered through a 0.22 micron
membrane into glass vials, capped, and autoclaved for
20 min at 121°C.
35
~d
37
EXAMPLE 51
Injections solutions containing 5-{N-(2-
hydroxyethyl)acetamido}-2,4,6-triiodo-3-{N-(1,3,4-
trihydroxy-threo-but-2-yl)}carbamoyl benzamide (11)
Iodine Content of Injection
Composition of 100 ml Solution in mg/ml
Aliquots of Solution 300 350 400
Compound (g) 58.87 68.68 78.49
Disodium, calcium salt of
ethylenediaminetetraacetic
acid (mg) 56 56 56
Trisodium citrate (mg) 77 77 77
Water for injection to
volume (ml) 100 100 100
Osmolality (mOsm/kg) 301 337 370
Viscosity at 37°C
(centipoise) 4.2 6.6 13.1
Procedure: The calcium-disodium salt of
ethylenediaminetetraacetic acid, trisodium citrate, and
the contrast media were dissolved in water for
injection and adjusted to pH 5.0 to 6.0 with sodium
carbonate and carbon dioxide. Solutions were QS'd to
100 ml with water for injection, filtered through a
0.22 micron membrane into glass vials, capped and
autoclaved for 20 minutes at 121°C.
It is evident from the above results, that
novel non-ionic contrast media are provided having
substantially superior properties to compounds
presently available. Because of the improvement in the
physical characteristics, particularly as to osmolality
and viscosity, a broad range of body regions may be
diagnosed while providing for easy administration and
lower pain. Despite the large number of compounds
which have been synthesized and tested, the subject
compounds are found to be superior to previously
disclosed compounds. By providing for three different
nitrogens in the molecule, only two of which are
substituted, 'the novel properties are achieved. In addition,
synthetic routes are provided which are efficient and provide for
high yields, while allowing for the use of readily available
materials.
- 38 -
