Note: Descriptions are shown in the official language in which they were submitted.
CA 02243316 1998-07-17
Metal Complexes that Contain Perfluoroalkyl, Procsss for their
Production and their Use in NMR Diagnosis
The invention relates to the subjects characterized in the
claims, i.e., new, monomeric, perfluoroalkyl-substituted,
paramagnetic metal complexes and complex salts, pharmaceutical
agents containing these metal complexes, processes for their
production, and their use as contrast media in 'H-NMR diagnosis
and 'H-NMR spectroscopy, diagnostic radiology, and radiodiagnosis
and as radiotherapeutic agents.
Nuclear magnetic resonance (NMR) is now a very extensively
used method of medical diagnosis, used for in vivo imaging, with
which vessels of the body and body tissue (including tumors) can
be visualized by measuring the magnetic properties of the protons
in the body water. To this end, e.g., contrast media are used
that produce contrast enhancement in the resulting images or make
these images readable by influencing specific NMR parameters of
the body protons (e. g., relaxation times T' and TZ). Mainly
complexes of paramagnetic ions, such as, e.g., gadolinium-
containing complexes (e.g., Magnevist~R~) are used owing to the
effect of the paramagnetic ions on the shortening of the
relaxation times. A measure of the shortening of the relaxation
time is relaxivity, which is indicated in mM'~ ' sec'' .
Paramagnetic ions, such as, e.g., Gd3', Mn2'', Cr3+, Fe3' and
Cu2' cannot be administered in free form as solutions since they
are too toxic. To make these ions suitable for in vivo use, they
CA 02243316 1998-07-17
2
are generally complexed, which is described for the first time in
EP 0 071 564 A1 (complexing with aminopolycarboxylic acids, e.g.,
with diethylenetriamine-pentaacetic acid [DTPA]). The di-N-
methylglucamine salt of the Gd-DTPA complex is known under the
name Magnevist~R~ and is used, i.a., to diagnose tumors in the
human brain and in the kidney.
The meglumine salt of Gd-DOTA (gadolinium(III) complex of
1,4,7,10-tetracarboxymethyl-1,4,7,10-tetraazacyclododecane) that
is described in French Patent 25 39 996 is another contrast
medium that has demonstrated its value in nuclear spin tomography
and was registered under the name Dotarem~R~.
These contrast media cannot be used, however, in a
satisfactory manner for all applications. Thus, the contrast
media used clinically at present for the modern imaging processes
of nuclear spin tomography (MRI) and computer tomography (CT),
such as, e.g., Magnevist~R~, Pro Hance~R~, Ultravist~R~ and
Omniscan~R~, are dispersed into the entire extracellular space of
the body (in the intravascular space and in the interstice).
Contrast media that also are dispersed exclusively in the
vascular space when administered in the latter and thus label it
(so-called blood-pool agents) are especially desirable, however,
for visualizing vessels.
An attempt was made to solve these problems by using
complexing agents, which are bonded to macromolecules or
biomolecules. Up until now, this has had very limited success.
CA 02243316 1998-07-17
3
Thus, for example, the number of paramagnetic centers in the
complexes that are described in EP 0 088 695 A1 and EP 0 150 844
A1 is inadequate for satisfactory imaging.
If the number of required metal ions is increased by
repeatedly introducing complexing units into a macromolecular
biomolecule, this is associated with an intolerable impairment of
the affinity and/or specificity of this biomolecule [J. Nucl.
Med. ~4_, 1158 (1983)].
Macromolecular contrast media for angiography, such as
albumin-Gd-DTPA, are described in Radiology _1.987; 162: 205.
Twenty-four hours after intravenous injection in rats, however,
albumin-Gd-DTPA shows a concentration in the liver tissue that
amounts to almost 30% of the dose. In addition, only 20% of the
dose is eliminated within 24 hours.
The macromolecule polylysine-Gd-DTPA (EP 0 233 619 A1) can
also be used as a blood-pool agent. For production reasons,
however, this compound consists of a mixture of molecules of
various sizes. In excretion tests in rats, it was possible to
show that this macromolecule is excreted unaltered by glomerular
filtration via the kidney. For synthesis reasons, it contains
polylysine-Gd-DTPA but also macromolecules that are so large that
they cannot pass through the capillaries of the kidney in the
case of glomerular filtration and thus remain in the body.
Macromolecular contrast media based on carbohydrates, e.g.,
dextran, have also been described (EP 0 326 226 A1). The
drawback of these compounds lies in the fact that the latter
CA 02243316 1998-07-17
4
generally have only about 5% of the signal-enhancing paramagnetic
cation.
The object of the invention was therefore to make available
new ~H-NMR contrast media that do not exhibit the above-mentioned
drawbacks and especially show a higher proton relaxivity and thus
allow a reduction of the dose with increased signal intensity.
The contrast media are also to be stable, well compatible and
mainly exhibit organ-specific properties, whereby, on the one
hand, their retention in the organs to be studied is to be
sufficient to obtain the number of images that is necessary for
an unambiguous diagnosis at low dosage, but, on the other hand,
an excretion of metals from the body that is as fast as possible
and very largely complete is then to be ensured.
The object of the invention is achieved with the monomeric,
perfluoroalkyl-containing compounds of general formula I
according to claim 1, which show a surprisingly high proton
relaxivity of 20-50 [mM-~ ' sec-~, 39°C, 0.47 T] . In comparison
with this, proton relaxivity for commercially available ~H-NMR
contrast media Magnevist~R~, Dotarem~R~, Omniscan~R~ and Pro Hance~R~
is between 3.5-4.9 [mM'~ ' sec's, 39°C, 0.47 T] .
In addition, the compounds according to the invention are
extremely well suited for detecting and locating vascular
diseases, since they are also exclusively dispersed in the latter
when administered in the intravascular space. The compounds
according to the invention make it possible to distinguish tissue
that is well-supplied with blood from tissue that is poorly
supplied With blood with the aid of nuclear spin tomography and
7(
CA 02243316 1998-07-17
thus to diagnose an ischemia. Infarcted tissue can also be
delimited from surrounding healthy or ischemic tissue due to its
anemia, if the contrast media according to the invention are
used. This is of special importance if the point is, e.g., to
distinguish a myocardial infarction from an ischemia.
Compared to the macromolecular compounds that were
previously used as blood-pool agents, such as, for example, Gd-
DTPA polylysine, the compounds according to the invention also
show a higher T' relaxivity (see Tab. 3) and are thus
distinguished by a large increase in signal intensity in the case
of NMR imaging. Since, in addition, they have an extended
retention in the blood space, they can also be administered in
relatively small dosages (of, e.g., <_ 50 ~mol of Gd/kg of body
weight). Mainly, however, the compounds according to the
invention, none of which are polymeric compounds, are eliminated
quickly and almost completely from the body.
It was also shown that the compounds of this invention are
suitable not only as blood-pool agents, but are also excellent
lymph-specific MRT contrast media (lymphographic agents).
The visualization of the lymph nodes is of vital importance
for early detection of metastatic invasion in cancer patients.
The contrast media according to the invention allow small
metastases in non-enlarged lymph nodes (< 2 cm) to be
distinguished from lymph node hyperplasias without malignant
invasions. In this case, the contrast media can be administered
intravascularly or interstitially/intracutaneously.
Interstitial/intracutaneous administration has the advantage that
CA 02243316 1998-07-17
6
the substance is transported directly from the scattering
concentrate table (e. g., primary tumor) via the corresponding
lymph tracts into the potentially affected regional lymph node
stations. Likewise, a high concentration of contrast medium in
the lymph nodes can be achieved with a small dose.
The compounds according to the invention meet all
requirements that are called for by contrast media in indirect
MRT lymphography: good local compatibility, quick elimination of
injection site, quick and very largely complete elimination from
the entire organism. They also show a high concentration over
several lymph node stations and thus make it possible to make
relevant diagnostic statements. Thus, in the guinea pig model,
it was possible to show a high concentration over several lymph
node stations (popliteal, inguinal, iliac) after s.c.
administration (2.5-10 ~mol/kg of body weight, injection in the
interdigital spaces of the hind paw). In especially suitable
cases, gadolinium concentrations of respectively >_ 200 or >_ 300
~mol/1 were obtained in the second (inguinal) and third (iliac)
stations. Usually, lymph node concentrations in the range of 100
to 1000 ~mol/1 can be obtained with the compounds according to
the invention.
It was possible to confirm the special suitability of the
compounds according to the invention in MR imaging studies in
guinea pigs. Thus, 120 minutes after subcutaneous administration
of 10 ~mol/kg of body weight of a perfluorine-containing
gadolinium complex (guinea pigs, hind paw, interdigital space) in
T~-weighted spin-echo images (TR 400 ms, TE 15 ms), a clear
CA 02243316 1998-07-17
7
enhancement of the popliteal lymph nodes (270%) as well as the
inguinal lymph nodes (104%) was observed (cf. Image 1).
In humans, the compounds according to the invention can be
injected locally (either subcutaneously or directly
percutaneously in the tissue of interest). Several injection
sites (weals) with a respective injection volume of 0.2 to 1 ml
are grouped around the areas of interest (e. g., tumor). In this
case, the injected total volume should not in any case exceed 5
ml. This means that in the formulation, a metal concentration of
75-100 mmol/1 must be present, so that a potential clinical dose
of 5-10 ~mol/kg of body weight can be administered with this
volume. The site of administration thereof depends on whether a
specific lymph outflow field from the tissue corresponding to it
is to be specifically stained (e. g., in the case of gynecological
or rectal tumors), or whether the unknown outflow field of a
certain lesion (ergo the area for a possible therapeutic
intervention, e.g., with melanoma or carcinoma of the breast) is
to be visualized.
In normal lymph node tissue, where the concentration of the
compound occurs, gadolinium concentrations of at least 50 ~mol/1
and at most 2500 ~mol/1 are required for MR imaging. The imaging
can be carried out (depending on injection site and tissue) after
30 minutes or up to 4-6 hours after injection of the compounds
according to the invention. Since mainly the T' relaxation times
of the protons of the water of the lymph node tissue are
influenced with the compounds of gadolinium complexes according
to the invention, T~-weighted sequences are best able to identify
~= CA 02243316 1998-07-17
8
an MRT enhancement of the lymph node stations. Since lymph nodes
very frequently are embedded in fatty tissue, and the latter has
a very high signal intensity in such sequences, fat-suppressed
measuring methods sugg~st themselves. Paramagnetic gadolinium
complexes in combination with fat-suppressed, T'-weighted
measuring sequences have the great advantage, compared to the
formulations of superparamagnetic iron oxide particles, that they
allow MRT images with greater spatial resolution, with fewer
distortion artifacts (based on susceptibility artifacts) and with
shorter imaging time.
Since positive labeling of the lymph nodes occurs (i.e.,
signal rise), MRT images without contrast media for comparison
are also no longer absolutely necessary, and the total
examination time per patient can be shortened.
The new perfluoroalkyl-containing compounds of general
formula I of claim 1 according to the invention comprise both
complexing agents and metal complexes. Compounds of general
formula I with Z' as a hydrogen atom are referred to as
complexing agents and compounds with at least one of possible
substituents Z~ as a metal ion equivalent are referred to as
metal complexes.
The compounds of general formula I according to the
CA 02243316 1998-07-17
9
invention contain, as preferred radical L, the following:
-CH~-
-CH~CH~-
-(CH2)s- s = 3 - 15
-CHI-O-CH~CH~-
-CHI-(O-CHI-CHZ-)t t = ? - 6
-CH2-NH-CO-
-CHZ-NH-CO-CH~-N(CH~COOH)-SO~-
-CH~-NH-CO-CH~-N(C~H~)-SO~-
-CHI-NH-CO-CHI-N(CIt~H~ 1)-SO~-
-CH~-NH-CO-CH~-N(C~~H 1;)-SO~-
-CH~-NH-CO-(CH~) lp-N(C~HS)-SO~-
-CH~-NH-CO-CH~-N(-CHZ-C~,H~)-SO~-
-CH~-NH-CO-CH~-N(-CH~-CH2-OH)SO~-
-CH~-NHCO-(CH~) lp-S-CH~CH2-
-CH~NHCOCH~-O-CH2CH~-
-CH~NHCO(CH~)lp-O-CH~CH~-
-CH~-C6H,~-O-CH~CH2-
-CH~-O-CH2-C(CH~-OCH~CH~-C6F13)~-CH~-OCH~-CH2-
-CHI-NHCOCH~CH2CON-CH~CH2NHCOCH~N(C~H~)SO~CgFl~
CH -CH NHCOCH~N(C H )-SO~
? _ 2 5
-CH2-O-CHI-CH(OClpH~ 1)-CHI-O-CH~CH~-
-(CH~NHCO)4-CH~O-CH~CH~-
-(CH~NHCO)3-CH~O-CH~CH~-
-CH~-OCH~C(CH~OH)2-CH~-O-CH~CH=-
-CHZ O / ~ CHz-O-CHz.-CHz
COOH
-CH~NHCOCH~N(C~H$)-s02-
-NHCO-CHI-CH~-
-NHCO-CH~-O-CH~CH~-
-NH-CO-
CA 02243316 1998-07-17
-NH-CO-CHI-N(CH~COOH)-SO~-
-N'H-CO-CHI-N(C~ H~)-SO~-
-NH-CO-CH~-N(ClpH~1)-SO~-
-NTH-CO-CH~-N(C6H 13)-SO~-
-\TH-CO-(CH2) 10-N(C~H~)-SO~-
-\ H-CO-CHI-N(-CHI-CGH~)-SO~-
-NH-CO-CH~-N(-CH~-CH~-OH)SO~-
-~'H-CO-CH~-
-CH~-O-C6Ha-O-CH~-CH~-
-CH~-C6H;1-O-CH~-CH~-
-\'(C?H~)-SO'_
-N(CGHS)-SO~_
-N(ClUH21 )-SO~-
-N'(C6H 13)-SO~-
-N(C~H~OH)-SO~-
-N(CH2COOH)-SO~-
-N(CH2C6H5)-SO~-
-N-[CH(CH~OH)~J-SO~-
-N-[CH(CH~OH)CH(CH~OH)J-S02-
According to the invention, radicals L of the compounds
mentioned in the examples of this description of the invention
are quite especially preferred.
CA 02243316 1998-07-17
11
Other preferred compounds are those in which X of the
formula -C~FZ~X means fluorine, and n stands for the numbers 4 to
15.
Compounds of general formula I with A in the meaning of
general formula IX, wh~reby L contains at least one -NHCO group,
can be obtained from compounds of general formula 14
COzZ'
N Ra
M~ NH2
Z ~02C
N N
OH
N
CO Z'
(14)
in which
R3 is in the above-mentioned meaning, Z~ is in the meaning
of a metal ion equivalent of atomic numbers 21-29, 39,
42, 44 or 57-83, and
M' is in the meaning of L,
by reaction with compounds of general formula 15
Nu M~ F
R
0 (1~)
CA 02243316 1998-07-17
12
in which
RF has the above-mentioned meaning,
M2 is in the meaning of L and
Nu is in the meaning of a nucleofuge.
Advantageously used as nucleofuges are the radicals:
CI, F, -OTs . -OMs .
F F
- - ~N /
_o \ ~ F , ~o ~ ~ Npa N~
N
I
F F O
NOz O
O \ / , O N
N O" O,
The reaction is carried out in a mixture of water and
organic solvents such as: isopropanol, ethanol, methanol,
butanol, dioxane, tetrahydrofuran, dimethylformamide,
dimethylacetamide, formamide or dichloromethane. Preferred are
ternary mixtures that consist of water, isopropanol and
dichloromethane.
The reaction is carried out at a temperature interval of
between -10°C - 100°C, preferably between 0°C -
30°C.
CA 02243316 1998-07-17
13
As acid traps, inorganic and organic bases such as
triethylamine, pyridine, N-methylmorpholine,
diisopropylethylamine, dimethylaminopyridine, alkali and
alkaline-earth hydroxides, their carbonates or bicarbonates such
as lithium hydroxide, sodium hydroxide, potassium hydroxide,
sodium carbonate, sodium bicarbonate and potassium bicarbonate
are used.
The compounds of general formula 15 are obtained from
compounds of general formula 16
HOZC-MZ-RF ' ( 16 )
in which
RF, M2 have the above-mentioned meaning, according to the
processes of acid activation that are generally known to one
skilled in the art, such as by reaction of the acid with
dicyclohexylcarbodiimide, N-hydroxysuccinimide/
dicyclohexylcarbodiimide, carbonyldiimidazole, 2-ethoxy-1-
ethoxycarbonyl-1,2-dihydroquinoline, oxalic acid dichloride or
isobutyl chloroformate according to the processes described in
the literature:
~ Aktivierung von Carbonsauren [Activation of Carboxylic
Acids]. ~bersicht in Houben-Weyl, Methoden der
organischen Chemie [Survey in Houben-Weyl, Methods of
Organic Chemistry], Volume XV/2, Georg Thieme Verlag
Stuttgart, 19.
~ Aktivierung mit Carbodiimiden [Activation with
Carbodiimides]. R. Schwyzer and H. Kappeler, Helv. 46:
1550 (1963).
CA 02243316 1998-07-17
14
~ E. Wiinsch et al., Volume ~ 173 (1967).
~ Aktivierung mit Carbodiimiden/Hydroxysuccinimid
[Activation with Carbodiimides/Hydroxysuccinimide]: J.
Am. Chem. Soc. 86: 1839 (1964) as well as J. Org.
Chem. ~3: 3583 (1988). Synthesis 453 (1972).
~ Anhydridmethode, 2-Ethoxy-1-ethoxycarbonyl-1,2-
dihydrochinolin [Anhydride Method, 2-Ethoxy-1-
ethoxycarbonyl-1,2-dihydroquinoline]: B. Belleau et
al., J. Am. Chem. Soc., ~0: 1651 (1986), H. Kunz et
al., Int. J. Pept. Prot. Res., ,~6: 493 (1985) and J.
R. Voughn, Am. Soc. 7~: 3547 {1951).
~ Imidazolid-Methode [Imidazolide Method]: B. F. Gisin,
R. B. Menifield, D. C. Tosteon, Am. Soc. 91: 2691
(1969).
~ Saurechlorid-Methoden, Thionylchlorid [Acid Chloride
Methods, Thionyl Chloride]: Helv., _4~: 1653 (1959).
~ Oxalylchlorid [Oxalyl Chloride]: J. Org. Chem., 29:
843 (1964).
The compounds of general formula 16 are commercially
available products (Fluorochem, ABCR) or are obtained from
compounds of general formula 17
H-Q-M3-RF ( 17 )
with
M3 in the meaning of L and
Q in the meaning of oxygen, sulfur, a > CO group, > N-R3,
R3-N-SO2 with a binding of a nitrogen atom to a
CA 02243316 1998-07-17
hydrogen atom,
by reaction with compounds of general formula 18
Hal-CH-C-OR°
' II
(18)
with
Hal meaning C1, Br, I and
R4 meaning H, methyl, ethyl, t-butyl, benzyl, isopropyl,
represented, for example, according to C. F. Ward, Soc.
1~, 1161 (1922), according to the methods known to one
skilled in the art, such as alkylation of alcohols with
alkyl halides [Houben-Weyl, Methoden der organischen
Chemie, Sauerstoffverbindungen [Oxygen Compounds] I,
Part 3, Methoden zur Herstellung and Umwandlung von
Ethern [Methods for the Production and Conversion of
Ethers], Georg Thieme Verlag, Stuttgart 1965,
Alkylierung von Alkoholen mit Alkylhalogeniden
[Alkylation of Alcohols with Alkyl Halides], p. 24,
Alkylierung von Alkoholen mit Alkylsulfaten [Alkylation
of Alcohols with Alkyl Sulfates] p. 33] or N-
Alkylierung eines Sulfonamids mit Alkylsulfonaten [N-
Alkylation of a Sulfonamide with Alkylsulfonates]
[Houben-Weyl, Methoden der organischen Chemie, XI/2
Stickstoffverbindungen [XI/2 Nitrogen Compounds], Georg
Thieme Verlag Stuttgart, 1957, p. 680; J. E. Rickman
and T. Atkins, Am. Chem. Soc., 96: 2268, 1974, 96:
2268; F. Chavez and A. D. Sherry, J. Org. Chem. 1989,
54: 2990].
-' CA 02243316 1998-07-17
16
If Q means a > CO group, the reaction is performed with a
Wittig reagent of the structure
+ -
(Ar)3 P-CH-(CHZ)~ C02R° ,
whereby r means numbers 0-16.
The -CH=CH double bond that is produced in this case can
remain as a component of the structure or be converted to a
-CHZ-CH2 group by catalytic hydrogenation (Pd 5%/C).
The compounds of general formula 18 are commercially
available products (Fluorochem, ABCR).
As an alternative, compounds of general formula I with A in
the meaning of general formula IX can be obtained from compounds
of general formula 19
COzR'
OH
RdOzC ~ wRF
~CO R'
(19)
with
RF, R3 and R4 in the above-mentioned meaning and
L' in the meaning of L, optionally with protected hydroxyl
or carboxyl functions,
CA 02243316 1998-07-17
17
by, if necessary, protective groups that are present being
cleaved and the thus obtained complexing agents being reacted
with metal oxides or metal salts at room temperature or elevated
temperature with the methods known according to one skilled in
the art (EP 250358, EP 255471), and then -- if desired -- acid
hydrogen atoms that are present being substituted by cations of
inorganic and/or organic bases, amino acids or amino acid amides.
The compounds of general formula 19 are obtained from
compounds of general formula 20 (D03A or the esters)
R'OZC~ ~ ~'C02R°
N N
N NH
C 0,. R'
' (?~)
with
R4 in the above-mentioned meaning
by reaction with compounds of general formula 21
3
R
O~ ~~ _'_' RF (21)
in which
CA 02243316 1998-07-17
18
R3 has the meaning of R', optionally in protected form, or
- ( CH2 ) m-L' -RF , whereby m is 0 , 1 or 2 , and L' and RF have the
above-mentioned meaning. The reaction is carried out in alcohols
such as methanol, ethanol, isopropanol, butanol, ethers such as
dioxane, tetrahydrofuran, dimethoxy ethers or in water or in
mixtures of water and one of the mentioned organic solvents, as
well as also acetonitrile, acetone, dimethylformamide,
dimethylacetamide or dimethyl sulfoxide, dichloromethane,
dichloroethane, chloroform at temperatures of between -10°C and
180°C, preferably at 20° - 100°C. The addition of organic
or
inorganic bases, such as triethylamine, pyridine,
dimethylaminopyridine, N-methylmorpholine, diisopropylamine,
alkali or alkaline-earth hydroxides or their carbonates or
bicarbonates such as lithium hydroxide, sodium hydroxide,
potassium hydroxide, sodium carbonate, potassium carbonate,
sodium bicarbonate and potassium bicarbonate, has proven
advantageous. In the case of low-boiling epoxides, the reaction
is carried out in an autoclave.
The compounds of general formula 21 are commercially
available products (Fluorochem, ABCR) or can be obtained from
compounds of general formula 22
R3-CH = CH-L'-RF (22)
by epoxidation according to the methods known to one skilled in
the art, for example, the wolframate-catalyzed oxidation with
HZOZ according to Payne, the cyclization of halohydrins or the
alkaline HZ02 oxidation in the presence of nitriles.
CA 02243316 1998-07-17
19
Especially suitable for this reaction is 3-chloroperbenzoic
acid in dichlorometha~ne at room temperature. Houben-Weyl,
Methoden der organischen Chemie, Sauerstoffverbindungen I, Part
3, Methoden zur Herstellung and Umwandlung dreigliedriger
cyclische Ether (1,2-Epoxide) [Methods for the Production and
Conversion of Three-Membered Cyclic Ethers (1,2-Epoxides)], Georg
Thieme Verlag, Stuttgart, 1965; G. B. Payne and P. H. Williams,
J. Org. Chem., 159, fig: 54; Y. Ogata and Y. Samaki, Tetrahedron
1964, ~0_: 2065; K. B. Sharpless et al., Pure Appl. Chem. 55, 589
(1983) .
Compounds of general formula 22 are preferably obtained by
Wittig reaction, or by the variants according to Horner,
Schlosser or Bestmann, Houben-Weyl, Methoden der organischen
Chemie XII/1, Organische Phosphorverbindungen Teil 1 [Organic
Phosphorus Compounds Part 1], Georg Thieme Verlag, Stuttgart,
1963, Phosphoniumsalze [Phosphonium Salts] p. 79,
Phosphoniumylide [Phosphonium Ylides] p. 112, Wittig Reaction
p. 121; A. W. Johnson, Ylides and Imines of Phosphorus, John
Wiley & Sons, Inc., New York, Chichester, Brisbane, Toronto,
Singapore, 1993, Wittig Reaction p. 221; Schlosser-Modifikation
der Wittig-Reaktion [Schlosser Modification of the Wittig
Reaction] p. 240; Wadsworth-Emmons-Reaktion [Wadsworth-Emmons
Reaction] p. 313; Horner Reaktion [Horner Reaction] p. 362, by
reaction of a triarylphosphonium ylide
Ari P-' CH-f-RF
X23)
CA 02243316 1998-07-17
with L' and RF in the above-mentioned meaning and Ar meaning
aryl, especially phenyl, with commercially available methods
(Merck, Fluka) or according to the methods known to one skilled
in the art, for example, oxidation of primary alcohols with
chromium trioxide/pyridine, Houben-Weyl, Methoden der organischen
Chemie, Sauerstoffverbindungen II, Part 1, Aldehyde [Aldehydes],
Georg Thieme Verlag, Stuttgart, 1954, aldehydes of general
formula 20 that can be produced
OHC-R3 (24)
whereby
R3 can also be H.
Triarylphosphonium ylides 23 are produced from the
corresponding halides of general formula 25
Hal-CH2-L' -RF ( 2 5 )
with Hal, L' and RF in the above-mentioned meaning according to
the methods known to one skilled in the art, for example by
heating the triarylphosphine with the alkylhalide, Houben-Weyl,
Methoden der organischen Chemie XII/1, Organische
Phosphorverbindungen Teil 1, Georg Thieme Verlag, Stuttgart, 1963
or A. W. Johnson, Ylides and Imines of Phosphorus, John Wiley &
Sons, Inc., New York, Chichester, Brisbane, Toronto, Singapore,
1993. The compounds of general formula 25 are commercially
available products (Fluorochem, ABCR, 3M).
The compounds of general formula 21 with R3 = H are
preferably obtained from compounds of general formula 17
H-Q ~ -M3-RF ( 17 )
in which
,,
CA 02243316 1998-07-17
21
Q' is in the meaning of Q, but cannot mean any > CO group,
M3 has the meaning of L with the exception of the direct
bond and
RF has the above-mentioned meaning,
by reaction according to the way of etherification or
sulfonamidealkylation with epihalohydrins that is known to one
skilled in the art: (Houben-Weyl, Methoden der organischen
Chemie, Sauerstoffverbindungen I, Part 3, Methoden zur
Herstellung and Umwandlung von Ethern, Georg Thieme Verlag,
Stuttgart, 1965, Alkylierung von Alkoholen [Alkylation of
Alcohols], pp. 24, 33; Houben-Weyl, Methoden der organischen
Chemie, XI/2 Stickstoffverbindungen, Georg Thieme Verlag,
Stuttgart, 1957, p. 680; J. E. Rickman and T. J. J. Atkins, Am.
Chem. Soc. 1974, 96: 2268; F. Chavez and A. D. Sherry, 1989, 54:
2990) of general formula 26
O
CH - Hal'
z (='~)
with
Hal' in the meaning of Hal, F, -OTs, OMs.
In the case of low-boiling epoxides, the reaction is carried
out in an autoclave.
Compounds of general formula I with A in the meaning of
general formula VIII ate obtained from compounds of general
CA 02243316 1998-07-17
22
formula 27
4
R OZC ~ ~ ~ COzR'
N N
0
N N ~ CHZCHz - L- R F
~N
Rz R3
COZR 4
with R2, R3, R4, L' and RF in the above-mentioned meaning,
by cleavage of optionally present protective groups and
complexing in the way known to one skilled in the art.
Compounds of general formula 27 are obtained by alkylation
of the compounds of general formula 20 with compounds of general
formula 28
R2
Hal
O
3
R- N
CHzCHz L~ ~ R F y
in which Hal, R2, R3, L' and RF have the above-mentioned meaning,
in a way known in the art, for example as described under EP 0
232 751 B1 (Squibb).
CA 02243316 1998-07-17
23
Compounds of general formula 28 are produced from compounds
of general formula 29
H \ N / CHZCHZ - ~\
RF
R3
(?9)
with L', R3 and RF in the above-mentioned meaning and an
activated halocarboxylic acid of general formula 30
2
R
CH
Nu -CO/ \ Hal
with Nu, RZ and Hal in the above-mentioned meaning
according to the methods of amide formation via activated
carboxylic acids that are known to one skilled in the art [cf.
Lit. p. 11].
Compounds of general formula 30 can be obtained from the
acids according to C. Hell, Vol. 14: 891 (1881); J. Volhard, A
242, 141 (1887); N. Zelinsky, Vol. 2~0: 2026, (1887) or from the
haloacids according to the activation methods as they are
described in general formula 15.
The compounds of general formula 29 can be easily produced
according to the methods of amine synthesis that are known to one
skilled in the art [Houben-Weyl, Methoden der organischen Chemie,
Stickstoffverbindungen II, Amino, 1st Run, Georg Thieme Verlag,
Stuttgart, 1957] from the commercially available compounds
Yr
CA 02243316 1998-07-17
24
(Fluorochem, ABCR) of general formula 31
Ha 1-CH2CH2-L' -RF ( 31 )
or 32
HO-CHZCHZ-L' -RF ( 3 2 )
for example by alkylation of a compound 31 with an amine
PhCHZNHR3 and subsequent deprotection of the amino group by
catalytic hydrogenation or by Mitsunobu reaction [H. Loibner and
E. Zbiral, Helv. 59, 2100 (1976), A. K. Bose and 8. Lal,
Tetrahedron Lett. 3973 (1973)] of a compound 32 with potassium
phthalimide and deprotection with hydrazine hydrate.
Compounds of general formula I with A in the meaning of
general formula VII are obtained from compounds of general
formula 33
R°02C
~N~
N
N\ /N "COY'
4 'r
COZR ~ wRF
(33)
with
L', RF and R4 in the above-mentioned meaning and
Y' in the meaning of Y, optionally with protective groups,
by cleavage of optionally present protective groups and
complexing according to the methods that are known to one skilled
in the art (Protective Groups in Organic Synthesis, 2nd Edition,
T. W. Greene and P. G. M. Wuts, John Wiley & Sons, Inc., New
York, 1991; EP 0 130 934, EP 0 250 358).
' CA 02243316 1998-07-17
Compounds of general formula 33 are obtained from compounds
of general formula 20 and compounds of general formula 34
O
Hal'
\ R (34)
in which
Hal', L', RF have the above-mentioned meaning and Y' stands
for the radical -off , -N-CHZ-CHz RF
R'
in a way known in the art, for example as described in EP 0 232
751 B1, EP 0 292 689 A2 (both Squibb) or EP 0 255 471 A1
(Schering).
The production of compounds of general formula 34 is carried
out according to known methods, for example, according to Hell-
Volhard-Zelinsky from commercially available precursors (ABCR).
Compounds of general formula I with A in the meaning of
general formula VI are obtained from compounds of general formula
R°OZC ~ ~ /~ COZR°
N N L'-RF
I°
COzR COZR
' CA 02243316 1998-07-17
26
in which L', R4 and RF have the above-mentioned meaning, by, if
appropriate, cleavage of protective groups and complexing in a
way known in the art [Protective Groups in Organic Synthesis, 2nd
Edition, T. W. Greene and P. G. M. Wuts, John Wiley & Sons, Inc.,
New York, 1991 (EP 0 130 934, EP 0 250 358)].
Compounds of general formula 35 are obtained by reacting a-
halocarboxylic acid esters or a-halocarboxylic acids of general
formula 18 with compounds of general formula 36
NH NH
NH NH ~L'-Rr
(36)
with L' and RF in the above-mentioned meaning, according to the
methods that are known to one skilled in the art, as described
in, for example, EP 0 255 471 or US 4,885,363.
Compounds of general formula 36 can be obtained by cleavage
of optionally present protective groups and subsequent reduction
with diborane according to the known processes from compounds of
CA 02243316 1998-07-17
27
general formula 37
N'H - N H- (CHZ)
0
F
f -R
N N H - (CH2) 4
K
(37)
in which
L', RF, o, q, have the above-mentioned meaning and
K has the meaning of a protective group.
The compounds of general formula 37 are available by a
condensation reaction from an activated, N-protected
iminodiacetic acid 38 and amine 39:
NuOC~ N ~CONu
K
(38)
N~NH
2
(CHZ) o
H2N
(CH2) 4 L-- R F
(39)
in which
CA 02243316 1998-07-17
28
L', RF, o, q, Nu and K have the above-mentioned meaning. As
a nucleofuge, preferably the N-hydroxysuccinimide is used; as a
protective group, the benzyloxycarbonyl, trifluoroacetyl or t-
butyloxycarbonyl group is used.
Compounds of general formula 38 can be obtained according to
the processes of protecting the amino group and of activating
carboxylic acid that are known to one skilled in the art
[Protective Groups, Aktivierung von Carboxylgruppen [Activation
of Carboxyl Groups], p. 11] with protected iminodiacetic acid 40
HOZC~NH~ COzH
K
(4U)
in which
K has the meaning of a protective group, from iminodiacetic
acid 41
HOzC~NH~CO~H (41)
As an alternative, compounds of general formula 36 are
available by, if appropriate, cleavage of protective groups and
reduction with diborane according to the process described in 37
CA 02243316 1998-07-17
29
from compounds of general formula 42
O
0 NH NH L'-R
NH NH 0
0 (4?')
Compounds of general formula 42 can be obtained by closing
the rings of Secco compounds 43
O
O NH NH
NHZ NH O
HO~
O// \L.-RF (43)
in which
L' and RF have the above-mentioned meaning, according to
standard processes; for example, by reaction with the Mukaiyama
reagent 2-fluoro-1-methylpyridinium-tosylate
i
\N F ~ Ts0-
I
CH3
CA 02243316 1998-07-17
[J. Org. Chem. 1994, 59, 415: Synthetic Communications 1995,
1401] or with the phosphoric acid diphenylester-azide
0
PhO~~~
/P-'N3
Ph0
[J. Am. Chem. Soc. 1993, 115, 3420; WO 94/15925].
Compounds of general formula 43 are available according to
the described processes by condensation of activated acid 44
O
K-HN ~~ ~CONu
NH
0 (44)
with Nu and K in the above-mentioned meaning, with a compound of
general formula 45
H2N L'-Rr
0
CO~R (4~)
in which
L', R4 and RF have the above-mentioned meaning.
Compounds of general formula 44 are available from
commercially available triglycine (Bachem, Fluka) 46
0 O
H2N~ NH~
NH~ OH
I0 (46)
by protection of the amino group with subsequent activation of
the acid function according to the processes for amine protection
CA 02243316 1998-07-17
31
and carboxylic acid reactivation that are known to one skilled in
the art (Lit. p. 12).
The compounds of general formula 45 can be easily obtained
from compounds of general formula 62 by introducing protective
group R4 according to the methods known to one skilled in the art
-- for example, re-este~rification of a sulfite ester.
Compounds of general formula I with A in the meaning of
general formula II are obtained from compounds of general formula
47
CHZCHZ L'-RF
NCO-N
3
R
a /~ ~C02R'
R OZC N
~CO~R'
N
COY' X47
with L', R3, R4, RF and Y' in the above-mentioned meaning, by, if
appropriate, cleavage of protective groups and complexing in a
way that is well-known to one skilled in the art (Protective
Groups, EP 0 250 358, EP 0 130 934).
If Y' in general formula 47 means an OH group, the compounds
CA 02243316 1998-07-17
32
are obtained by reacting a compound 48
~~0
~bb'N
N ~ COZH
~--- COZH
N
~ COZR°
with R4 in the above-mentioned meaning, produced according to DE
3 633 243, with an amine of general formula 29 under the
conditions already described and subsequent cleavage of the
protective groups.
If Y' in formula 47, however, is the group -N-CH CH-L'-RF
z z
R'
then the reaction is performed under analogous conditions with
DTPA-bisanhydride (commercially available product, Merck) 49
,O
" N
~O
HOZC~N ~,~,~~0
O
N
-O
(~9)
Compounds of general formula I, with A in the meaning of
general formula III, are obtained from compounds of general
CA 02243316 1998-07-17
33
formula 50
COzRa
3 N
R Rz
COZR 4
N
N
COzRa
0
N
COZR °
(50)
in which
L' , RZ, R3, R4 and RF have the above-mentioned meaning, by,
if appropriate, cleavage of protective groups and complexing in a
way that is well-known to one skilled in the art [Protective
Groups, EP 0 071564, EP 0 130 934, DE-OS 3 401 052].
Compounds of general formula 50 are obtained according to
the process described in J. Org. Chem. 1993, ,~8: 1151 from
compounds of general formula 51
Rs Rz
. ~ N ~NHz
R~ L
0 (
and halocarboxylic acid derivatives of formula 52
'CO2R'
HaI~NI ~COzR'
(~~)
CA 02243316 1998-07-17
34
in which R4 and Hal have the already described meaning. The
compounds of general formula 51 are produced by acylation of an
amine of general formula 29 with an activated N-protected amino
acid of general formula 53
NuCO--CH-NH "i(
RZ (53)
in which Nu has the above-mentioned meaning and K is in the
meaning of a protective group such as Z, -BOC, FMOC, -COCF3, and
subsequent cleavage of the protective group.
Compounds of general formula I with A in the meaning of
general formula IV are obtained from compounds of general formula
54
CO R° N ~ COzR°
z
F ,
R \L~~O \CO2R°
N
/ COZR°
N
~COzR° ~54)
in which
L', RF and R4 have the above-mentioned meaning, by, if
appropriate, cleavage of the protective groups and complexing
according to a method that is known to one skilled in the art, as
already described [Protective Groups, EP 0 071 564, EP 0 130 934,
DE-OS 3 401 052].
Compounds of general formula 54 can be obtained in a known
way from the halogen compounds of general formula 55
' CA 02243316 1998-07-17
Hal-L'-RF (55)
that can be obtained as commercially available products
(Fluorochem, ABCR) by reaction with hydroxy acids 56
CO R' N~C02R'
HBO ~COZR'
N
~-COZR°
N
~COZR°
(56)
in which
R4 has the above-mentioned meaning. The compounds of
formula 56 can be obtained in a way known in the art according to
J. Org. Chem. 58, 1151 (1993) from commercially available serine
ester 57 (Bachem, Fluka)
COZR°
HO~
NHZ (~?)
with R4 in the above-mentioned meaning and halocarboxylic acid
esters 58
HaI~N~CO R°
z
COZR° (~b)
Compounds of general formula I with A in the meaning of
CA 02243316 1998-07-17
36
general formula V are obtained from compounds of general formula
59
COzR a
N
R4 ~ ~ COzR 4
OzC N
(CHz)o
~CHz)
4
L, ~ N /'~ COzR a
RF
COzR °
(59)
in which
L', o, q, R4 and RF have the above-mentioned meaning, by, if
appropriate, cleavage of protective groups and complexing
according to a method that is known to one skilled in the art.
[Protective Groups, EP 0 071 564, EP 0 130 934, DE-OS 3 401 052].
Compounds of general formula 59 can be produced in a known
way, for example, according to J. Org. Chem., ~$, 1151 (1993), by
reaction of halocarboxylic acid esters 18
Hal-CHZCOZR4 ( 18 )
with Hal and R4 in the above-mentioned meaning, and a compound of
' CA 02243316 1998-07-17
37
general formula 39
NHZ
NH
[CHI o
~CH~ q
\ NH2
L'
R F (39)
in which
L', o, q, and Rf have the above-mentioned meaning.
The compounds of general formula 39 are obtained for the
case q = 0 from the compounds of general formula 60
NH2
NH
O
NH-K
L'
RF
(60)
with
L', RF and K in the above-mentioned meaning,
in a way known in the art [Helv. Chim. Acta, 77: 23 (1994)] by
reduction with diborane and cleavage of the protective groups.
The compounds of general formula 60 are obtained with
ethylenediamine by aminolysis of the activated compounds of
CA 02243316 1998-07-17
38
general formula 61
RF- L'- CH-NH-K
CONu ( 61 )
in which
L', Nu, RF and K have the above-mentioned meaning.
The compounds of general formula 61 are produced according
to the known methods of protective group chemistry [Protective
Groups] from the unprotected acid of general formula 62
RF L'-CH-NH2
COZH ( 62 )
specifically the amino group is protected in a first step,
followed by the activation of the acid group in the second step.
The compounds of general formula 62 can be produced
according to the methods of amino acid synthesis [Houben-Weyl,
Methoden der organischen Chemie, XI/2 Stickstoffverbindungen II
and III, II Aminosauren [II Amino Acids]; Georg Thieme Verlag
Stuttgart, 1958, Strecker-Reaktion [Strecker Reaction], p. 305;
Erlenmeyer-Reaktion [Erlenmeyer Reaction], p. 306; Aminolyse von
a-Halogencarbonsauren [Aminolysis of a-Halocarboxylic Acids],
p. 309] from the commercially available aldehydes of general
formula 63
HOC-L'._RF ( 63 )
for example, according to Strecker, via the azlactone or via the
cyanohydrin.
The compounds of general formula 39 are obtained for the
' CA 02243316 1998-07-17
39
case o = 0 from the compounds of general formula 64
RF L'-CH-NHCO-CH2-NH--fC
(64)
CO-NHz
with RF, L' and K in the mentioned meanings,
in a way known in the art by cleavage of the protective groups
and reduction with diborane.
Compounds of general formula 64 are available by aminolysis
of N-protected, activated glycines 53 with compounds of general
formula 65
RF L'- i H-NH2
CO-NH2 ( 65 )
in which RF and L' have the mentioned meanings.
The compounds of general formula 65 can be obtained in a
simple way from compounds of general formula 61 by amide
formation with ammonia and subsequent cleavage of the protective
group.
Compounds of general formula XIII can be produced
analogously to the compounds of general formula III, by
halocarboxylic acid derivatives of general formula 52 being
reacted with a compound of general formula 66
RF L'-SOZ-N N-O-CH-NH2
(66)
in which RF, L' and RZ have the above-mentioned meanings.
' CA 02243316 1998-07-17
The compounds of general formula 66 are produced by reaction
of a compound of general formula 67
F
R-L'-SOZ-N _N- H
(67)
with the activated, N-protected amino acid of general formula 53
analogously to the reaction of amine 29 with compound 53.
The compounds of general formula 67 can be obtained by
reaction of piperazine -- freely or optionally partially
protected -- with perfluoroalkylsulfonic acid fluorides or
-chlorides. (The sulfonamide formation from amine and
sulfofluoride is described in DOS 2 118 190, DOS 2 153 270, both
Bayer AG).
Compounds of general formula XI with q meaning number 0 or 1
are produced analogously to compounds of general formula VIII, by
compounds of general formula 20 being reacted with compounds of
general formula 68
O
RF L'-SO - ~ _.'
z ~ C- CH- Hal
R2
(68)
in which RF, L', R2 and Hal have the above-mentioned meaning,
- CA 02243316 1998-07-17
41
or with compounds of general formula 68a
O
R -L-SOi N N-C-CH2-(CH2)p NH-C- i H-Hal
R (68a)
in which RF, L', RZ, p and Hal have the above-mentioned meanings.
Compounds of general formula 68 can be obtained from
compounds of general formula 30 and piperazine derivatives of
general formula 67 in a way known in the art.
Compounds of general formula 68a can be obtained from
compounds of general formula 67 by amide coupling with compounds
of general formula 68b
HOOC-CHZ (CH2)P-NH-CO-CHRZ-Hal (68b) .
Compounds of general formula XII are produced analogously to
compounds of general formula II, e.g., by reaction of compounds
of formula 49 with piperazine derivatives of general formula 67.
Compounds of general formula I with A in the meaning of
general formula X are obtained from compounds of general formula
69
4
COZR
N N
~ Sg
O
N
N_ , R 3
\~/ L'
COZR ~
R (69)
CA 02243316 1998-07-17
42
in which
L', R3, R4 and RF have the above-described meaning and Sg is
in the meaning of a protective group,
by, if appropriate, cleavage of protective groups and complexing
in a way known in the art [Protective Groups in Organic
Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, John
Wiley & Sons, Inc., New York, 1991 (EP 0 130 934, EP 0 250 358)].
Compounds of general formula 69 are obtained by reaction of
a-halocarboxylic acid esters or a-halocarboxylic acids of general
formula 18 with compounds of general formula 70
N~NH
Sg
O
NH N
W R3
L'
IF
R (70)
with L', RF, R3 and Sg in the above-mentioned meaning
according to the methods that are known to one skilled in the
art, as described in, for example, EP 0 255 471 or US 4,885,363.
Compounds of general formula 70 can be obtained by cleavage
of optionally present protective groups and subsequent reduction
with diborane according to the known processes from compounds of
CA 02243316 1998-07-17
43
general formula 71
N' - N H 0
H
Sg
0
NH N
wRs
/ L'
IF
(71)
in which
L', RF, R3 and Sg have the above-mentioned meaning.
The compounds of general formula 71 can be obtained by a
condensation reaction from an activated iminodiacetic acid
derivative of general formula 72 and the diethylenetriamine of
formula 73
O / S9
O
Nu
N Rs
L'
Nu \RF
O (72)
HZN
N-H
H2N
(73)
-' CA 02243316 1998-07-17
44
in which
L', RF, R3, Sg and Nu have the above-mentioned meaning.
N-Hydroxysuccinimide is preferably used as nucleofuge Nu.
Compounds of general formula 72 can be obtained from
compounds of general formula 74
O / S9
O
HO~
~3
N
L'
HO I I \ R F
O (74)
in which
L', RF and Sg have the above-mentioned meaning, by
activation of carboxylic acids, as described on page 11.
Compounds of general formula 74 are obtained by reaction of
a-halocarboxylic acid esters or a-halocarboxylic acids of general
formula 18 with compounds of general formula 75
O-Sg
H2N R3
L'
IF
(75)
in which
L', RF, R3 and Sg have the above-mentioned meaning,
whereby optionally present ester groups are saponified.
CA 02243316 1998-07-17
Compounds of general formula 75 are obtained from compounds
of general formula 76
O- Sg
K-NH
'R
L'
IF
R (76)
in which
L', RF, R3, Sg and K have the above-mentioned meaning,
by cleavage of protective group K according to the known
processes.
Compounds of general formula 76 are obtained from compounds
of general formula 77
OH
K-NH
'R
L'
IF
R (77)
in which
L', RF, R3 and K have the above-mentioned meaning,
by introduction of a protective group Sg in the way known to one
skilled in the art.
Compounds of general formula 77 are obtained from the
CA 02243316 1998-07-17
46
compounds of general formula 78
K-NH CHO
L'
IF
(78)
in which
L', RF and K have the above-mentioned meaning,
according to the methods that are well-known to one skilled in
the art (Houben-Weyl, Methoden der organischen Chemie, XIII 2a,
Metallorganische Verbindungen [Organornetallic Compounds], Georg
Thieme Verlag Stuttgart, 1973, p. 285 ff, Umsetzung
magnesiumorganischer Verbindungen mit Aldehyden [Reaction of
Magnesium-Organic Compounds with Aldehydes]); p. 809 ff,
Umsetzung von zinkorganischen Verbindungen mit Aldehyden
[Reaction of Zinc-Organic Compounds with Aldehydes]; Houben-Weyl,
Methoden der organischen Chemie XIII/1, Metallorganische
Verbindungen, Georg Thieme Verlag Stuttgart, 1970; p. 175 ff,
Umsetzung lithiumorganischer Verbindungen mit Aldehyden [Reaction
of Lithium-Organic Compounds with Aldehydes] by reaction with the
organometallic compounds, such as magnesium, lithium or zinc
compounds, that can be obtained from compounds of general formula
79
Ha l ~-R3 ( 7 9 )
in which
Hal and R3 have the above-mentioned meaning.
CA 02243316 1998-07-17
47
Compounds of general formula 79 are commercially available
products (ABCR, Fluka).
Compounds of general formula 78 are produced from compounds
of general formula 80
K-NH COZMe
L~
RF
(80)
in which
L', RF and K have the above-mentioned meaning,
by reduction with diisobutylaluminum hydride (Tett. Lett., 1962,
619; Tett. Lett., 1969, 1779; Synthesis, 1975, 617).
Compounds of general formula 80 are produced from compounds
of general formula 45
H2N COZMe
L'
~F
R
(45)
in which
L' and RF have the above-mentioned meaning,
in a way known to one skilled in the art by introducing
protective group K.
The neutralization of optionally still present free carboxy
groups is done with the aid of inorganic bases (for example,
hydroxides, carbonates or bicarbonates) of, for example, sodium,
potassium, lithium, magnesium or calcium and/or organic bases
CA 02243316 1998-07-17
48
such as, i.a., primary, secondary and tertiary amines, such as,
for example, ethanolamine, morpholine, glucamine, N-
methylglucamine and N,N-dimethylglucamine, as well as basic amino
acids, such as, for example, lysine, arginine and ornithine or of
amides of originally neutral or acidic amino acids.
To produce neutral complex compounds, enough of the desired
bases can be added to, for example, the acidic complex salts in
aqueous solution or suspension to ensure that the neutral point
is reached. The solution obtained can then be evaporated to the
dry state in a vacuum. Often, it is advantageous to precipitate
the neutral salts formed by adding water-miscible solvents, such
as, for example, lower alcohols (methanol, ethanol, isopropanol,
etc.), lower ketones (acetone, etc.), polar ethers
(tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.) and to
obtain easily isolated and readily purified crystallizates. It
has proven especially advantageous to add the desired base as
early as during the complexing of the reaction mixture and thus
to save a process step.
Pharmaceutical agents that contain at least one
physiologically compatible compound of general formula I,
optionally with the additives that are commonly used in
galenicals, are also the subject of the invention.
The production of the pharmaceutical agents according to the
invention is carried out in a way known in the art, by the
complex compounds according to the invention -- optionally with
the addition of the additives that are commonly used in
galenicals -- being suspended or dissolved in aqueous medium and
CA 02243316 1998-07-17
49
then the suspension or solution optionally being sterilized.
Suitable additives are, for example, physiologically harmless
buffers (such as, for example, tromethamine), additions of
complexing agents or weak complexes (such as, for example,
diethylenetriaminepentaacetic acid or the Ca complexes that
correspond to the metal complexes according to the invention) or
-- if necessary -- electrolytes, such as, for example, sodium
chloride or -- if necessary -- antioxidants such as, for example,
ascorbic acid.
If suspensions or solutions of the agents according to the
invention in water or physiological salt solution are desired for
enteral or parenteral administration or other purposes, they are
mixed with one or more adjuvant(s) that are commonly used in
galenicals [for example, methyl cellulose, lactose, mannitol]
and/or surfactant (s) [for example, lecithins, Tween~R~, Myrj~R~]
and/or flavoring substances) for taste correction [for example,
ethereal oils].
In principle, it is also possible to produce the
pharmaceutical agents according to the invention without
isolating the complexes. In any case, special care must be used
to undertake the chelation so that the complexes according to the
invention are practically free from noncomplexed metal ions that
have a toxic effect.
This can be ensured, for example, with the aid of color
indicators such as xylenol orange by control titrations during
the production process. The invention therefore also relates to
the process for the production of complex compounds and their
CA 02243316 1998-07-17
salts. As a final precaution, there remains purification of the
isolated complex.
The pharmaceutical agents according to the invention
preferably contain 0.1 ~mol - 1 mol/1 of the complex and are
generally dosed in amounts of 0.0001-5 mmol/kg. They are
intended for enteral and parenteral administration. The complex
compounds according to the invention are used
1. for NMR diagnosis and diagnostic radiology in the form
of their complexes with the ions of elements with
atomic numbers 21-29, 39, 42, 44 and 57-83;
2. for radiodiagnosis and radiotherapy in the form of
their complexes with the radioisotopes of the elements
with atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62,
64, 70, 75 and 77.
The agents according to the invention meet the varied
requirements for suitability as contrast media for nuclear spin
tomography. Thus, after oral or parenteral administration and by
increasing the signal intensity, they are extremely well suited
to improve in its informative value the image obtained with the
aid of the nuclear spin tomograph. They also show the high
effectiveness that is necessary to burden the body with the
smallest possible amounts of foreign substances, and the good
compatibility that is necessary to maintain the noninvasive
nature of the studies.
The good water-solubility and low osmolality of the agents
according to the invention make it possible to produce highly-
concentrated solutions, thus to keep the volume burden of the
CA 02243316 1998-07-17
51
circulatory system within justifiable limits and to offset the
dilution by the bodily fluid. In addition, the agents according
to the invention exhibit not only high stability in vitro, but
also surprisingly high stability in vivo, so that a release or an
exchange of the ions that are bonded to the complexes -- and
toxic in themselves -- is carried out only extremely slowly
within the time in which the new contrast media are completely
eliminated again.
In general, the agents according to the invention for use as
NMR diagnostic agents are dosed in amounts of 0.0001 - 5 mmol/kg,
preferably 0.005 - 0.5 mmol/kg. Especially low dosages (below 1
mg/kg of body weight) of organ-specific NMR diagnostic agents can
be used, for example, for detecting tumors and myocardial
infarctions.
The complex compounds according to the invention can also be
used advantageously as susceptibility reagents and as shift
reagents for in vivo NMR spectroscopy.
The agents according to the invention are also suitable as
radiodiagnostic agents owing to their advantageous radioactive
properties and the good stability of the complex compounds that
are contained in them. Details of such use and dosage are
described in, e.g., "Ra~diotracers for Medical Applications," CRC
Press, Boca Raton, Florida.
The compounds and agents according to the invention can also
be used in positron emission tomography, which uses positron-
emitting isotopes such as, e.g., 43Sc, 44Sc, 52Fe, 55Co and ~Ga
CA 02243316 1998-07-17
52
(Heiss, W. D.; Phelps, M. E.; Positron Emission Tomography of
Brain, Springer Verlag Berlin, Heidelberg, New York 1983).
The compounds according to the invention are also suitable,
surprisingly enough, for differentiating malignant and benign
tumors in areas without blood-brain barriers.
They are also distinguished in that they are eliminated
completely from the body and are thus well compatible.
Since the substances according to the invention accumulate
in malignant tumors (no diffusion in healthy tissue, but high
permeability of tumor vessels), they can also assist the
radiation therapy of malignant tumors. The latter are
distinguished from the corresponding diagnosis only by the amount
and type of isotope used. In this case, the aim is the
destruction of tumor cells by high-energy shortwave radiation
with as small a range of action as possible. For this purpose,
interactions of the metals that are contained in the complexes
(such as, e.g., iron or gadolinium) with ionizing radiations
(e. g., x rays) or with neutron rays are employed. The local
radiation dose at the site where the metal complex is located
(e.g., in tumors), is significantly enhanced by this effect. To
produce the same radiation dose in malignant tissue, the
radiation exposure for healthy tissue can be considerably reduced
and thus burdensome side effects for the patients can be avoided
when such metal complexes are used. The metal complex conjugates
according to the invention are therefore also suitable as
radiosensitizing substances in the case of radiation therapy of
malignant tumors (e. g., use of Mossbauer effects or in the case
CA 02243316 1998-07-17
53
of neutron capture therapy). Suitable !3-emitting ions are, for
example, 46Sc, 47Sc, 48Sc, 7zGa, ~Ga and 9°Y. Suitable a-emitting
ions that exhibit short half-lives are, for example, z~~Bi, z~zBi,
z~3Bi and z~4Bl, whereby z~zBi is preferred. A suitable photon- and
electron-emitting ion is ~58Gd, which can be obtained from ~57Gd by
neutron capture.
If the agent according to the invention is specified for use
in the variant of radiation therapy that is proposed by R. L.
Mills et al. (Nature Vol. 336, (1988), p. 787J, the central ion
must be derived from a Mossbauer isotope, such as, for example,
S~Fe or ~S~Eu.
In the case of in vivo administration of the agents
according to the invention, the latter can be administered
together with a suitable vehicle, such as, for example, serum or
physiological common salt solution and together with another
protein such as, for example, human serum albumin. In this case,
the dosage is dependent on the type of cellular impairment, the
metal ion used and the type of imaging method.
The agents according to the invention are usually
administered parenterally, preferably i.v. They can also be
administered -- as already discussed -- intravascularly or
interstitially/intracutaneously, depending on how the vessels or
tissue of the body are to be examined.
The agents according to the invention are extremely well
suited as x-ray contrast media, in which case it is especially to
be emphasized that with them, no signs of the anaphylaxis-like
reactions that are known from the iodine-containing contrast
CA 02243316 1998-07-17
54
media can be detected in biochemical-pharmacological studies.
They are especially valuable because of the advantageous
absorption properties in the ranges of higher tube voltages for
digital substraction techniques.
In general, the agents according to the invention for use as
x-ray contrast media are dosed, for example, analogously to
meglumine-diatrizoate, in amounts of 0.1 - 5 mmol/kg, preferably
0.25 - 1 mmol/kg.
Taken overall, it has been possible to synthesize new
complexing agents, metal complexes and metal complex salts to
open up new possibilities in diagnostic and therapeutic medicine.
The following examples are used for a more detailed
explanation of the subject of the invention:
CA 02243316 1998-07-17
Example 1
a) N-Ethyl-N-(perfluorooctylsulfonyl)-amino-acetic acid-t-butyl
ester
20 g (37.94 mmol) of N-ethylperfluorooctylsulfonamide and
15.73 g (113.8 mmol) of potassium carbonate are suspended in 200
ml of acetone, and 14.80 g (75.87 mmol) of bromoacetic acid-tert-
butyl ester is added in drops at 60°C. It is stirred for 3 hours
at 60°C. The salts are filtered out, and the filtrate is
evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent: hexane/
dichloromethane/acetone = 10/10/1). After the product-containing
fractions are concentrated by evaporation, the residue is
recrystallized from methanol/ether.
Yield: 21.66 g (89% of theory) of a waxy, colorless solid
Elementary analysis:
Cld: C 29.96 H 2.51 F 50.36 N 2.18 S 5.00
Fnd: C 29.81 H 2.70 F 50.15 N 2.30 S 4.83
b) N-Ethyl-N-(perfluorooctylsulfonyl)-amino-acetic acid
20 g (31.18 mmol) of the title compound of Example la) is
dissolved in 200 ml of trifluoroacetic acid and stirred overnight
at room temperature. It is evaporated to the dry state in a
vacuum. The residue is recrystallized from methanol/ether.
Yield: 17.34 g (95% of~theory) of a colorless,
crystalline solid
CA 02243316 1998-07-17
56
Elementary analysis:
Cld: C 24.63 H 1.38 F 55.19 N 2.39 S 5.48
Fnd: C 24.48 H 1.50 F 55.01 N 2.17 S 5.59
c) Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-aza-7-
(perfluorooctylsulfonyl)-nonyl]-1,4,7-tris(carboxymethyl)-
1,4,7,10-tetraazacyclododecane
g (17.09 mmol) of the title compound of Example 1b) and
1.97 g (18.79 mmol) of N-hydroxysuccinimide are dissolved in a
mixture of 50 ml of dimethylformamide/50 ml of chloroform. At
0°C, 3.88 g (18.79 mmol) of dicyclohexylcarbodiimide is added and
stirred for 1 hour at 0°C, then for 3 hours at room temperature.
It is cooled again to 0°C, and 5.19 g (51.27 mmol) of
triethylamine/50 ml of 2-propanol is added. Then, 10.78 g (18.79
mmol) of the gadolinium complex of 10-(3-amino-2-hydroxy-propyl)-
1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (WO
95/17451), dissolved in 50 ml of water, is added and stirred for
3 hours at room temperature. It is evaporated to the dry state,
the residue is taken up in a mixture of 200 ml of methanol/100 ml
of chloroform, and dicyclohexylurea is filtered out. The
filtrate is evaporated to the dry state and purified by RP-
chromatography (RP-18/mobile solvent: gradient consisting of
water/n-propanol/acetonitrile).
Yield: 16.37 g (78% of theory) of a colorless, vitreous
solid
Water content: 7.1%
CA 02243316 1998-07-17
57
T~-relaxivity (L/mmol~sec) at 20 MHz, 37°C:
41 (water)
49 (human plasma)
Elementary analysis (relative to anhydrous substance):
Cld: C 30.58 H 3.18 F 28.31 Gd 13.78 N 7.37 S 2.81
Fnd: C 30.40 H 3.29 F 28.14 Gd 13.55 N 7.28 S 2.65
d) l0-[2-Hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctylsulfonyl)-
nonyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane
g (8.76 mmol) of the title compound of Example lc) is
dissolved in a mixture of 100 ml of water/100 ml of ethanol, and
1.73 g (13:71 mmol) of oxalic acid-dihydrate is added. It is
heated for 8 hours to 80°C. It is cooled to 0°C, and
precipitated gadolinium oxalate is filtered out. The filtrate is
evaporated to the dry state, and the residue is purified on RP-18
(RP-18/mobile solvent: gradient consisting of water/i-
propanol/acetonitrile).
Yield: 8.96 g (94% of theory) of a vitreous solid
Water content: 9.3%
Elementary analysis (relative to anhydrous substance):
Cld: C 35.30 H 3.98 F 32.73 N 8.52 S 3.25
Fnd: C 35.10 H 4.15 F 32.51 N 8.35 S 3.15
CA 02243316 1998-07-17
58
e) Manganese complex of 10-[2-hydroxy-4-aza-5-oxo-7-aza-7-
(perfluorooctylsulfonyl)-nonyl]-1,4,7-tris(carboxymethyl)-
1,4,7,10-tetraazacyclododecane (as sodium salt)
g (5.07 mmol) of the title compound of Example 1d) is
dissolved in 100 ml of water, and 0.58 g (5.07 mmol) of
manganese(II) carbonate is added. It is stirred for 3 hours at
80°C. The solution is filtered, and the filtrate is set at pH
7.2 with 1N sodium hydroxide solution, then it is freeze-dried.
Yield: 5.87 g (quantitative) of a colorless, amorphous
powder
Water content: 8.4~
T~-relaxivity (L/mmol~sec) at 20 MHz, 37°C:
2.7 (water)
4.2 (human plasma)
Elementary analysis (relative to anhydrous substance):
Cld: C 32.81 H 3.42 F 30.42 Mn 5.17 N 7.92 Na 2.17 S 3.02
Fnd: C 32.62 H 3.57 F 30.21 Mn 5.06 N 7.80 Na 2.01 S 2.90
f) Ytterbium complex of 10-[2-hydroxy-4-aza-5-oxo-7-aza-7-
(perfluorooctyl-sulfonyl)-nonyl]-1,4,7-tris(carboxymethyl)-
1,4,7,10-tetraazacyclododecane
1.33 g (2.53 mmol) of ytterbium carbonate is added to 5 g
(5.07 mmol) of the title compound of Example id) in 100 ml of
water/30 ml of ethanol, and it is stirred for 3 hours at 80°C.
The solution is filtered, and the filtrate is evaporated to the
dry state in a vacuum.
CA 02243316 1998-07-17
59
Yield: 6.36 q (quantitative) of a vitreous solid.
Water content: 7.8%
Elementary analysis (relative to anhydrous substance):
Cld: C 30.11 H 3.14 F 27.92 N 7.27 S 2.77 Yb 14.96
Fnd: C 30.02 H 3.27 F 27.80 N 7.10 S 2.68 Yb 14.75
g) Dysprosium complex of 10-[2-hydroxy-4-aza-5-oxo-7-aza-7-
(perfluorooctylsulfonyl)-nonyl]-1,4,7-tris(carboxymethyl)-
1,4,7,10-tetraazacyclododecane
0.95 g (2.53 mmol) of dysprosium oxide is added to 5 g (5.07
mmol) of the title compound of Example 1d) in 100 ml of water/30
ml of ethanol, and it is stirred for 3 hours at 80°C. The
solution is filtered, and the filtrate is evaporated to the dry
state in a vacuum.
Yield: 6.35 g (quantitative) of a colorless, vitreous solid.
Water content: 8.5%.
Elementary analysis (relative to anhydrous substance):
Cld: C 30.39 H 3.17 F 28.18 N 7.33 S 2.80 Dy 14.18
Fnd: C 30.17 H 3.25 F 28.03 N 7.21 S 2.65 Dy 14.00
Example 2
a) 13,13,13,12,12,11,11,10,10,9,9,8,8,7,7,6,6-Heptadecafluoro-
3-oxatridecanoic acid-t-butyl ester
10.51 g (53.9 mmol) of bromoacetic acid-tert-butyl ester is
added in drops to a mixture of 10 g (21.55 mmol) of 1H,1H,2H,2H-
CA 02243316 1998-07-17
perfluorodecan-1-of and 0.73 g (2.15 mmol) of tetrabutylammonium
hydrogen sulfate in 100 ml of 60% potassium hydroxide solution/50
ml of toluene while being stirred vigorously at 0°C. It is
stirred for 1 hour at 0°C. 200 ml of toluene is added, the
aqueous phase is separated and extracted twice with 50 ml of
toluene each. The combined organic phases are dried on magnesium
sulfate and concentrated by evaporation in a vacuum. The residue
is chromatographed on silica gel (mobile solvent:
hexane/dichloromethane/acetone = 20/10/1).
Yield: 9.72 g (78% of theory) of a colorless, viscous oil
Elementary analysis:
Cld: C 33.23 H 2.61 F 55.85
Fnd: C 33.09 H 2.78 F 55.71
b) 13,13,13,12,12,11,11,10,10,9,9,8,8,7,7,6,6-Heptadecafluoro-
3-oxatridecanoic acid
9.0 g (15.56 mmol) of the title compound of Example 2a) is
dissolved in 180 ml of trifluoroacetic acid and stirred overnight
at room temperature. It is evaporated to the dry state in a
vacuum. The residue is recrystallized from methanol/ether.
Yield: 7.80 g (96% of theory) of a colorless solid
Elementary analysis:
Cld: C 27.60 H 1.35 F 61.85
Fnd: C 27.48 H 1.49 F 61.66
CA 02243316 1998-07-17
61
c) Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-oxa-
10,10,11,11,12,12,13,13,14,14,15,15,16,16,17,17,17-
heptadecafluoroheptadecyl]-1,4,7-tris(carboxymethyl)-
1,4,7,10-tetraazacyclododecane
7.0 g (13.41 mmol) of the title compound of Example 2b) and
1.70 g (14.75 mmol) of N-hydroxysuccinimide are dissolved in a
mixture of 30 ml of dimethylformamide/20 ml of chloroform. At
0°C, 3.04 g (14.75 mmol) of dicyclohexylcarbodiimide is added and
stirred for 1 hour at 0°C, then for 3 hours at room temperature.
It is cooled again to 0°C, and 4.48 g (44.25 mmol) of
triethylamine/50 ml of 2-propanol is added. Then, 8.46 g (14.75
mmol) of the gadolinium complex of 10-(3-amino-2-hydroxy-propyl)-
1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane,
dissolved in 40 ml of water, is added and stirred for 3 hours at
room temperature. It is evaporated to the dry state, the residue
is taken up in a mixture of 100 ml of methanol/30 ml of
chloroform, and dicyclohexylurea is filtered out. The filtrate
is evaporated to the dry state and purified by RP-chromatography
(RP-18/mobile solvent: gradient consisting of water/n-
propanol/acetonitrile).
Yield: 11.8 g (75% of theory) of a colorless, vitreous
solid
Water content: 8.2%
T~-relaxivity (L/mmol~sec) at 20 MHz, 37°C:
19 (water)
33 (human plasma)
CA 02243316 1998-07-17
62
Elementary analysis:
Cld: C 32.32 H 3.27 F 29.96 Gd 14.59 N 6.50
Fnd: C 32.16 H 3.42 F 29.78 Gd 14.39 N 6.40
Example 3
a) 1,2-Epoxy-4-oxa-1H,1H,2H,3H,3H,5H,5H,6H,6H-
perfluorotetradecane
7.97 g (86.18 mmol) of epichlorohydrin is added in drops to
a mixture of 20 g (43.09 mmol) of 1H,1H,2H,2H-perfluorodecan- 1-of
and 0.79 g (2.32 mmol) of tetrabutylammonium hydrogen sulfate in
200 ml of 60% potassium hydroxide solution/100 ml of toluene
while being stirred vigorously at 10C, and care is taken to
ensure that the temperature of the reaction solution is not
higher than 20C. It is allowed to stir for 2 hours at 15C, and
then 3.99 g (43.09 mmol) of epichlorohydrin is added in drops as
described above. Then, it is stirred overnight at room
temperature. 100 ml of methyl-tert-butyl ether is added, and the
aqueous phase is separated. The latter is extracted twice mo re
with 50 ml of toluene each. The organic phases are combined,
dried on magnesium sulfate and concentrated by evaporation a
in
vacuum. The residue i~t chromatographed on silica gel (mobile
solvent: dichloromethane/hexane/acetone = 20/10/1).
Yield: 19.05 g (85% of theory) of a colorless oil
Elementary analysis:
Cld: C 30.02 H 1.74 F 62.09
Fnd: C 29.87 H 1.95 F 61.81
CA 02243316 1998-07-17
63
b) 10-[-2Hydroxy-4-oxa-1H,1H,2H,3H,3H,5H,5H,6H,6H-
perfluorotetradecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane
8.3 g (207.6 mmol) of sodium hydroxide is added to 12.0 g
(34.60 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane in 50 ml of water. A solution of 18.0 g
(34.60 mmol) of the title compound of Example 3a), dissolved in
60 ml of n-butanol/60 ml of 2-propanol, is added dropwise to it,
and the solution is heated overnight to 70°C. It is evaporated
to the dry state in a vacuum, the residue is taken up in 300 ml
of water and set at pH 3 with 3N hydrochloric acid. Then, it is
extracted twice with 200 ml of n-butanol. The combined butanol
phases are evaporated to the dry state in a vacuum, and the
residue is purified by RP-chromatography (RP-18/mobile solvent:
gradient consisting of water/n-butanol/acetonitrile).
Yield: 26.61 g (79% of theory)
Water content: 11.0%
Elementary analysis (relative to anhydrous substance):
Cld: C 37.42 H 4.07 F 37.27 N 6.47
Fnd: C 37.25 H 4.19 F 37.08 N 6.30
c) Gadolinium complex of 10-[-2hydroxy-4-oxa-
1H,1H,2H,3H,3H,5H,5H,6H,6H-perfluorotetradecyl]-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
g (11.54 mmol) of the title compound of Example 3b) is
dissolved in a mixture of 100 ml of water/50 ml of 2-propanol,
CA 02243316 1998-07-17
64
and 2.09 g (5.77 mmol) of gadolinium oxide is added. It is
stirred for 3 hours at 80°C. The solution is filtered and
evaporated to the dry state in a vacuum.
Yield: 12.48 g (quantitative) of a vitreous solid
Water content: 5.6%
T~-relaxivity (L/mmol-sec) at 20 MHz, 37°C:
15.2 (water)
27.5 (human plasma)
Elementary analysis (relative to anhydrous substance):
Cld: C 31.77 H 3.16 F 31.64 Gd 15.40 N 5.49
Fnd: C 31.55 H 3.30 F 31.49 Gd 15.28 N 5.35
Example 4
a) 1,2-Epoxy-4-oxa-1H,1H,2H,3H,3H,5H,5H,6H,6H-perfluorododecane
10.17 g (109.9 mmol) of epichlorohydrin is added in drops to
a mixture of 20 g (54.93 mmol) of 1H,1H,2H,2H-perfluorooctan-1-of
and 1.87 g (5.5 mmol) of tetrabutylammonium hydrogen sulfate in
200 ml of 60% aqueous potassium hydroxide solution/100 ml of
toluene while being stirred vigorously at 10°C, and care is taken
to ensure that the temperature of the reaction solution is not
higher than 20°C. It is allowed to stir for 2 hours at 15°C, and
then 5.08 g (54.93 mmol) of epichlorohydrin is added in drops as
described above. Then, it is stirred overnight at room
temperature. 100 ml of toluene and 100 ml of methyl-tert-butyl
ether are added, and the aqueous phase is separated. The latter
is extracted twice more with 50 ml of toluene each. The organic
CA 02243316 1998-07-17
phases are combined, dried on magnesium sulfate and concentrated
by evaporation in a vacuum. The residue is chromatographed on
silica gel (mobile solvent: dichloromethane/hexane/acetone =
20/10/1).
Yield: 19.15 g (83% of theory) of a colorless oil
Elementary analysis:
Cld: C 31.44 H 2.16 F 58.78
Fnd: C 31.40 H 2.29 F 58.55
b) 10-[2-Hydroxy-4-oxa-iH,lH,2H,3H,3H,5H,5H,6H,6H-
perfluorododecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane
10.3 g (257 mmol) of sodium hydroxide is added to 14.84 g
(42.84 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane (D03A) in 70 ml of water. A solution of 18
g (42.84 mmol) of the title compound of Example 4a), dissolved in
80 ml of n-butanol/60 mol of 2-propanol, is added dropwise to it,
and the solution is heated overnight to 70°C. It is evaporated
to the dry state in a vacuum, the residue is taken up in 300 ml
of water and set at pH 3 with 3N hydrochloric acid. Then, it is
extracted twice with 200 ml of n-butanol. The combined butanol
phases are evaporated to the dry state in a vacuum, and the
residue is purified by RP-chromatography (RP-18/mobile solvent:
gradient consisting of water/n-butanol/acetonitrile).
Yield: 27.4 g (75% of theory) of a vitreous solid
Water content: 10.1%
CA 02243316 1998-07-17
66
Elementary analysis (relative to anhydrous substance):
Cld: C 39.17 H 4.60 F 32.22 N 7.31
Fnd: C 39.05 H 4.85 F 32.05 N 7.19
c) Gadolinium complex of 10-[2-hydroxy-4-oxa-
1H,1H,2H,3H,3H,5H,5H,6H,6H-perfluorododecyl]-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
g (13.04 mmol) of the title compound of Example 4b) is
dissolved in a mixture of 100 ml of water/50 ml of 2-propanol,
and 2.36 g (6.52 mmol) of gadolinium oxide is added. It is
stirred for 3 hours at 80°C. The solution is filtered and
evaporated to the dry state in a vacuum.
Yield: 12.77 g (quantitative) of a vitreous solid
Water content: 6.1%
Elementary analysis (relative to anhydrous substance):
Cld: C 32.61 H 3.50 F 26.82 Gd 17.08 N 6.08
Fnd: C 32.43 H 3.69 F 26.67 Gd 16.85 N 5.91
Euample 5
a) 9,9,9,8,8,?,7,6,6-Nonafluoro-3-oxa-nonanoic acid-t-butyl
ester
29.54 g (151.5 mmol) of bromoacetic acid-tert-butyl ester is
added in drops to a mixture of 20 g (75.73 mmol) of iH,lH,2H,2H-
perfluorohexan-1-of and 2.57 g (7.57 mmol) of tetrabutylammonium
hydrogen sulfate in 300 ml of 60% aqueous potassium hydroxide
solution/200 ml of toluene while being stirred vigorously at 0°C.
CA 02243316 1998-07-17
67
It is stirred for 1 hour at 0°C. 100 ml of toluene is added, the
aqueous phase is separated and extracted twice with 50 ml of
toluene. The combined organic phases are dried on magnesium
sulfate and concentrated by evaporation in a vacuum. The residue
is chromatographed on silica gel (mobile solvent:
hexane/dichloromethane/acetone = 20/10/1).
Yield: 21.48 g (75% of theory) of a colorless oil
Elementary analysis:
Cld: C 38.11 H 4.00 F 45.21
Fnd: C 37.95 H 4.18 F 45.03
b) 9,9,9,8,8,7,7,6,6-Nonanefluoro-3-oxa-nonanoic acid
20 g (52.88 mmol) of the title compound of Example 5a) is
dissolved in 300 ml of trifluoroacetic acid and stirred overnight
at room temperature. It is evaporated to the dry state in a
vacuum. The residue is recrystallized from hexane/ether.
Yield: 14.82 g (87% of theory) of a colorless,
crystalline solid
Elementary analysis:
Cld: C 29.83 H 2.19 F 53.08
Fnd: C 29.71 H 2.40 F 52.90
c) Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-oxa-
10,10,11,11,12,12,13,13,13-nonafluoro-tridecyl]-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
CA 02243316 1998-07-17
68
7.41 g (23.01 mmol) of the title compound of Example 5b) and
2.91 g (25.31 mmol) of N-hydroxysuccinimide are dissolved in a
mixture of 40 ml of dimethylformamide/20 ml of chloroform. At
0°C, 5.22 g (25.31 mmol) of dicyclohexylcarbodiimide is added and
stirred for 1 hour at 0°C, then for 3 hours at room temperature.
It is cooled again to 0°C, and 6.98 g (69 mmol) of
triethylamine/30 ml of 2-propanol is added. Then, 13.2 g (23.01
mmol) of the gadolinium complex of 10-(3-amino-2-hydroxy-propyl)-
1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclodododecane,
dissolved in 40 ml of water, is added and stirred for 3 hours at
room temperature. It is evaporated to the dry state, the residue
is taken up in a mixture of 200 ml of methanol/50 ml of
chloroform, and cyclohexylurea is filtered out. The filtrate is
evaporated to the dry state and purified by RP-chromatography
(RP-18/mobile solvent: gradient consisting of water/n-
propanol/acetonitrile).
Yield: 15.20 g (71% of theory) of a colorless, vitreous
solid
Water content: 5.7%
Elementary analysis (relative to anhydrous substance):
Cld: C 34.21 H 4.02 F 19.48 Gd 17.91 N 7.98
Fnd: C 34.09 H 4.18 F 19.31 Gd 17.74 N 7.87
$zample 6
a) N-Ethyl-N-(perfluorooctylsulfonyl)-amino-acetic acid-N-(2-
aminoethyl)-amide
CA 02243316 1998-07-17
69
15 g (25.63 mmol) of the title compound of Example 1b) and
3.24 g (28.19 mmol) of N-hydroxysuccinimide are dissolved in 80
ml of dimethylformamide, and 5.82 g (28.19 mmol) of
dicyclohexylcarbodiimide is added at 0°C. It is stirred for 1
hour at 0°C, then for 2 hours at room temperature. Precipitated
dicyclohexylurea is filtered out, and the filtrate is added in
drops within 30 minutes to a solution of 46.21 g (768.9 mmol) of
ethylenediamine in 300 ml of dichloromethane. It is stirred for
hours at room temperature. 1000 ml of HZO is added, and the
organic phase is separated. The latter is washed twice with 500
ml of water each, then dried on magnesium sulfate and evaporated
to the dry state in a vacuum. The purification is carried out by
chromatography on silica gel. (Mobile solvent: dichloromethane/
2-propanol = 15/1).
Yield: 11.79 g (75% of theory) of a colorless, waxy solid
Elementary analysis:
Cld: C 27.42 H 2.30 F 52.66 N 4.57 S 5.23
Fnd: C 27.20 H 2.41 F 52.48 N 4.38 S 5.10
b) N-Ethyl-N-(perfluorooctylsulfonyl)-amino-acetic acid-N-[2-
(bromoacetyl)-aminoethyl]-amide
g (16.3 mmol) of the title compound of Example 6a) and
2.02 g (20 mmol) of triethylamine are dissolved in 40 ml of
dichloromethane. At -10°C, 3.29 g (16.3 mmol) of bromoacetyl
bromide is added in drops within 30 minutes and stirred for 2
hours at 0°C. The solution is poured into 30o ml of 1N
CA 02243316 1998-07-17
hydrochloric acid and stirred thoroughly. The organic phase is
separated, dried on magnesium sulfate and concentrated by
evaporation in a vacuum. The residue is chromatographed on
silica gel (mobile solvent: dichloromethane/acetone = 20/1).
Yield: 11.1 g (91% of theory) of a slightly yellow-
colored waxy solid
Elementary analysis:
Cld: C 25.68 H 2.02 Br 10.68 F 43.16 N 5.62 S 4.29
Fnd: C 25.47 H 2.18 Br 10.45 F 43.29 N 5.47 S 4.10
c) 10-[2-Oxo-3-aza-6-aza-7-oxo-9-aza-9-
(perfluorooctylsulfonyl)-undecyl]-1,4,7-tris(carboxymethyl)-
1,4,7,10-tetraazacyclododecane
4.63 g (13.36 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane (D03A) and 18.5 g (133.6 mmol) of potassium
carbonate are added to 10 g (13.36 mmol) of the title compound of
Example 6b) in 180 ml of methanol. It is refluxed for 12 hours.
The inorganic salts are filtered off, and the filtrate is
evaporated to the dry state. The residue is taken up in 100 ml
of water and set at pH 3 with 5N hydrochloric acid. It is
extracted twice with 150 ml of n-butanol. The combined organic
phases are evaporated to the dry state in a vacuum, and the
residue is purified by RP-chromatography (RP-18/mobile solvent =
gradient consisting of water/n-butanol/acetonitrile).
Yield: 10.43 g (67% of theory) of a colorless solid
Water content: 13.0%
CA 02243316 1998-07-17
71
Elementary analysis (relative to anhydrous substance):
Cld: C 35.55 H 3.98 F 31.86 N 9.67 S 3.16
Fnd: C 35.37 H 3.75 F 31.64 N 9.78 S 3.25
d) Gadolinium complex of 10-[2-oxo-3-aza-6-aza-7-oxo-9-aza-9-
(perfluorooctyl6ulfonyl)-undecyl]-1,4,7-tris(carboxymethyl)-
1,4,7,10-tetraazacyclododecane
g (9.86 mmol) of the title compound of Example 6c) is
dissolved in a mixture of 50 ml of water/20 ml of ethanol, and
1.79 g (4.93 mmol) of gadolinium oxide is added. It is stirred
for 4 hours at 80°C. The solution is filtered and evaporated to
the dry state in a vacuum.
Yield: 12.4 g (quantitative)
Water content: 7.1%
Elementary analysis (relative to anhydrous substance):
Cld: C 30.85 H 3.19 F 27.65 Gd 13.46 N 8.39 S 2.75
Fnd: C 30.64 H 3.35 F 27.58 Gd 13.29 N 8.28 S 2.65
CA 02243316 1998-07-17
72
E:ample 7
a) 1H,1H,2H,2H-Perfluorodecan-1-ol-p-toluenesulfonic acid ester
12.57 g (65.93 mmol) of p-toluenesulfonic acid chloride is
added to 30 g (64.64 mmol) of iH,iH,2H,2H-perfluorodecan-1-of in
300 ml of dichloromethane and 10.12 g (100 mmol) of triethylamine
at 0°C. It is stirred for 2 hours at 0°C, then for 2 hours at
room temperature. The solution is poured into 500 ml of cold 2N
hydrochloric acid and stirred vigorously. The organic phase is
separated, dried on magnesium sulfate and evaporated to the dry
state. The residue is recrystallized from a little methanol.
Yield: 39.97 (95% of theory) of a colorless, crystalline
powder
Elementary analysis:
Cld: C 33.02 H 1.79 F 52.23 S 5.19
Fnd: C 32.81 H 1.93 F 52.04 S 5.05
b) 10-[(1-Hydroxymethyl-1-carboxy)-methyl]-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
37.2 g (173.4 mmol) of 2-chloro-3-benzyloxy-propanoic acid
is added to a solution of 20 g (57.78 mmol) of 1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (D03A), 31.21
g (780 mmol) of sodium hydroxide and 2 g (12 mmol) of potassium
iodide in 100 ml of dimethylformamide, and it is stirred for 3
days at 60°C. It is evaporated to the dry state, and the residue
is dissolved in 300 ml of water. Then, it is set at pH 3 with 3N
hydrochloric acid and extracted twice with 250 ml of
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73
dichloromethane each. 4 g of palladium catalyst (10% Pd/C) is
added to the aqueous phase and hydrogenated for 5 hours at 60°C.
The catalyst is filtered off, and the filtrate is evaporated to
the dry state. The residue is purified by RP-chromatography (RP-
18/mobile solvent = gradient consisting of water/2-
propanol/acetonitrile).
Yield: 5.92 g (21% of theory relative to D03A) of a
colorless, vitreous solid
Water content: 11.1%
Elementary analysis (relative to anhydrous substance):
Cld: C 47.00 H 6.96 N 12.90
Fnd: C 46.81 H 6.78 N 12.99
c) 10-[1-Hydroxymethyl-1-(methoxycarbonyl)-methyl]-1,4,7-
tris(methoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane
9.53 g (80 mmol) of thionyl chloride is added in drops to
200 ml of methanol at 0°C. Then, 5.8 g (13.35 mmol) of the title
compound of Example 7b) is added and stirred for 1 hour at 0°C.
Then, it is heated for 6 hours to 60°C. It is evaporated to the
dry state, the residue is taken up in 150 ml of methylene
chloride and extracted 3 times with 200 ml of 8% aqueous soda
solution each. The organic phase is dried on magnesium sulfate
and evaporated to the dry state. 6.09 g (93% of theory) of the
title compound is obtained as a slightly yellowish-colored oil.
CA 02243316 1998-07-17
74
Elementary analysis:
Cld: C 51.42 H 7.81 N 11.42
Fnd: C 51.20 H 7.95 N 11.28
d) 10-[1-(Methoxycarbonyl)-3-oxa-iH,2H,2H,4H,4H,5H,5H-
perfluorotridecyl]-1,4,7-tris(methoxycarbonylmethyl)-
1,4,7,10-tetraazacyclododecane
0.44 g (14.68 mmol) of sodium hydride (80% suspension in
mineral oil) is added to 6 g (12.23 mmol) of the title compound
of Example 7c) in 40 m1 of dimethylformamide and stirred for 30
minutes at -10°C. Then, 8.32 g (13.45 mmol) of the title
compound of Example 7a) is added and stirred for 8 hours at room
temperature. 400 ml of ice water is carefully added and
extracted twice with 300 ml of ethyl acetate each. The combined
ethyl acetate phases are washed with saturated aqueous common
salt solution and dried on magnesium sulfate. It is evaporated
to the dry state in a vacuum, and the residue is chromatographed
on silica gel (mobile solvent: dichloromethane/methanol = 20/1).
Yield: 7.68 g (67% of theory) of a viscous yellow oil
Elementary analysis:
Cld: C 39.75 H 4.41 F 34.48 N 5.98
Fnd: C 39.58 H 4.60 F 34.27 N 5.75
CA 02243316 1998-07-17
e) 10-(1-Carboxy-3-oxa-iH,2H,2H,4H,4H,5H,5H-perfluorotridecyl]-
1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
7.5 g (8.01 mmol) of the title compound of Example 7d) is
suspended in a mixture of 50 ml of water/30 ml of ethanol, and
then 3.84 g (96 mmol) of sodium hydroxide is added. It is
refluxed overnight. It is cooled to room temperature and set at
pH 3 with 3N hydrochloric acid. It is evaporated to the dry
state in a vacuum, and the residue is purified by RP-
chromatography (RP-18/mobile solvent = gradient consisting of
water/n-butanol/acetonitrile).
Yield: 6.84 g (87% of theory) of a vitreous solid
Water content: 10.3$
Elementary analysis (relative to anhydrous substance):
Cld: C 36.83 H 3.78 F 36.68 N 6.36
Fnd: C 36.67 H 3.90 F 36.49 N 6.25
f) Gadolinium complex of 10-[1-carboxy-3-oxa-
iH,2H,2H,4H,4H,5H,5H-perfluorotridecyl]1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (as
sodium salt)
6 g (6.81 mmol) of the title compound of Example 7e) is
suspended in 80 ml of water, and 1.23 g (3.4 mmol) of gadolinium
oxide is added. It is heated for 3 hours to 90°C. It is allowed
to cool to room temperature and set at pH 7.2 with 2N sodium
hydroxide solution. The solution is filtered and then freeze-
dried.
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76
Yield: 7.83 g (quantitative) of a colorless, flocculent
powder
water content: 8.1%
Elementary analysis (relative to anhydrous substance):
Cld: C 30.69 H 2.77 F 30.56 Gd 14.88 N 5.30 Na 2.18
Fnd: C 30.48 H 2.85 F 30.37 Gd 14.69 N 5.17 Na 1.95
Buampla 8
a) 2H,2H-Perfluorooctanal
30 g (82.4 mmol) of iH,iH,2H,2H-perfluorooctan-1-of is
dissolved in 500 ml of dichloromethane, and 17.76 g (82.4 mmol)
of pyridinium chlorochromate is added. It is stirred overnight
at room temperature. The solution is filtered with a short
column, filled with aluminum oxide (neutral), the filtrate is
evaporated to the dry state and the residue is chromatographed on
silica gel (mobile solvent: dichloromethane/hexane/acetone =
10/10/1).
Yield: 26.55 g (89% of theory) of a waxy solid
Elementary analysis:
Cld: C 26.54 H 0.84 F 68.21
Fnd: C 26.47 H 1.05 F 68.10
b) 2-Amino-2H,3H,3H-perfluorononanoic acid (as hydrochloride)
7.04 g (143.6 mmol) of sodium cyanide and 8.45 g (158 mmol)
of ammonium chloride are dissolved in 30 ml of water. 40 ml of
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77
ethanol and 26 g (71.8 mmol) of the title compound of Example 8a)
are added to this solution. It is heated for 2 hours to 45°C.
300 ml of water is added, and it is extracted 3 times with 200 ml
of benzene each. The combined benzene phases are washed 3 times
with 200 ml of water emch, and the organic phase is evaporated to
the dry state in a vacuum. The residue is taken up in 100 ml of
6N aqueous hydrochloric acid/50 ml of methanol and refluxed for 2
hours. It is evaporated to the dry state in a vacuum. The
residue is recrystallized from a little 2-propanol/methyl-tert-
butyl ether.
Yield: 11.15 g (35% of theory) of a crystalline solid
Elementary analysis:
Cld: C 24.37 H 1.59 C1 7.99 F 55.68 N 3.16
Fnd: C 24.15 H 1.72 C1 7.65 F 55.51 N 3.05
c) 2-[(N-Benzyloxycarbonyl)-triglycidyl]-amino-2H,3H,3H-
perfluorononanoic acid
8.37 g (24.8 mmol) of N-benzyloxycarbonyl-triglycine and
3.14 g (27.28 mmol) of N-hydroxysuccinimide are dissolved in 80
ml of dimethylformamide, and 5.63 g (27.28 mmol) of
dicyclohexylcarbodiimide is added at 0°C. It is stirred for 1
hour at 0°C, then for 2 hours at room temperature. It is cooled
to 0°C, 7.53 g (74.4 mmol) of triethylamine and 11 g (24.8 mmol)
of the title compound of Example 8b are added and then stirred
overnight at room temgerature. It is evaporated to the dry state
in a vacuum, the residue is taken up in 300 ml of 5% aqueous
CA 02243316 1998-07-17
78
citric acid and extracted 3 times with 200 ml of ethyl acetate
each. The combined organic phases are dried on magnesium sulfate
and evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent: dichloromethane/
n-propanol=20/1).
Yield: 11.83 g (67% of theory) of a colorless, sheetlike
solid
Elementary analysis:
Cld: C 38.78 H 2.97 F 34.67 N 7.86
Fnd: C 38.59 H 2.85 F 34.48 N 7.91
d) 2-[Triglycidyl]-amino-2H,3H,3H-perfluorononanoic acid
11.5 g (16.14 mmol) of the title compound of Example 8c) is
dissolved in 200 ml of 2-propanol, and 3 g of palladium catalyst
(10% Pd/C) is added. It is hydrogenated overnight at room
temperature. Catalyst is filtered out, and the filtrate is
evaporated to the dry state.
Yield: 9.33 g (quantitative) of a colorless solid
Elementary analysis:
Cld: C 31.15 H 2.61 F 42.71 N 9.69
Fnd: C 31.29 H 2.80 F 42.53 N 9.48
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79
e) 2-(1H,1H-Perfluoroheptyl)-1,4,7,10-tetraaza-3,6,9,12-
tetraoxo-cyclododecane
9.2 g (15.91 mmol) of the title compound of Example 8d) is
dissolved in 1000 ml of dimethylformamide, and 3.93 g (15.91
mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added.
It is stirred for 3 days at room temperature. It is evaporated
to the dry state, and the residue is chromatographed on silica
gel (mobile solvent: dichloromethane/2-propanol = 20/1).
Yield: 4.54 g (51% of theory) of a waxy solid
Elementary analysis:
Cld: C 32.16 H 2.34 F 44.08 N 10.00
Fnd: C 32.05 H 2.47 F 43.87 N 9.89
f) 2-(1H,1H-Perfluoroheptyl)-1,4,7,10-tetraazacyclododecane (as
tetrahydrochloride)
200 ml of 1M borane-tetrahydrofuran complex solution is
added to 4.4 g (7.85 mmol) of the title compound of Example 8e)
and refluxed for 2 days. It is evaporated to the dry state in a
vacuum, and the residue is taken up in 50 ml of concentrated
hydrochloric acid. 100 ml of ethanol is added, and it is
refluxed for 8 hours. It is evaporated to the dry state in a
vacuum, and the residue is recrystallized from ethanol.
Yield: 4.75 g (93% of theory) of a colorless, crystalline
powder
CA 02243316 1998-07-17
Elementary analysis:
Cld: C 27.71 H 3.88 C1 21.81 F 37.99 N 8.62
Fnd: C 27.65 H 3.95 C1 21.40 F 37.69 N 8.41
g) 2-(lH,iH-Perfluoroheptyl)-1,4,7,10-tetra(carboxymethyl)-
1,4,7,10-tetraazacyclododecane
4.6 g (7.07 mmol) of the title compound of Example 8f) and
4.0 g (42.4 mmol) of chloroacetic acid are dissolved in 40 ml of
water, and the pH is set at 10 by adding 30% aqueous potassium
hydroxide solution. It is heated far 8 hours to 70°C and in this
case, the pH is kept between 8 and 10 (by adding 30% aqueous
potassium hydroxide solution). The solution is cooled to room
temperature, set at pH 2 with concentrated hydrochloric acid and
evaporated to the dry state. The residue is taken up in 150 ml
of methanol, the salts are filtered off, and the filtrate is
evaporated to the dry state in a vacuum. The residue is purified
by RP-18 chromatography (RP-18/mobile solvent: gradient
consisting of water/2-propanol/acetonitrile).
Yield: 5.03 g (87% of theory) of a vitreous solid
Water content: 10.1%
Elementary analysis (relative to anhydrous substance):
Cld: C 37.51 H 3.97 F 33.53 N 7.61
Fnd: C 37.35 H 4.12 F 33.40 N 7.45
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81
h) Gadolinium complex of 2-(1H,1H-perfluoroheptyl)-1,4,7,10-
tetra(carboxymethyl)-1,4,7,10-tetraazacyclododecane (as
sodium salt)
4.5 g (6.11 mmol) of the title compound of Example 8g) is
suspended in 100 ml of water, and 1.107 g (3.05 mmol) of
gadolinium oxide is added. It is heated for 3 hours to 90°C. It
is allowed to cool to room temperature and set at pH 7.2 with 2N
sodium hydroxide solution. The solution is filtered and then
freeze-dried.
Yield: 6.03 g (quantitative) of a colorless powder
Water content: 7.5%
Elementary analysis (relative to anhydrous substance):
Cld: C 30.23 H 2.87 F 27.03 Gd 17.21 N 6.13 Na 2.52
Fnd: C 30.10 H 3.05 F 26.81 Gd 17.15 N 5.95 Na 2.30
Euample 9
a) 10-[2-Hydroxy-1H,1H,2H,3H,3H-perfluorononyl]-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
13.85 g (346.4 mmol) of sodium hydroxide is added to 15 g
(43.3 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane in 50 ml of water. A solution of 27.68 g
(64.95 mmol) of 1,2-epoxy-1H,1H,2H,3H,3H-perfluorononane,
dissolved in 50 ml of n-butanol/50 ml of 2-propanol, is added
dropwise to it, and the solution is heated overnight to 80°C. It
is evaporated to the dry state in a vacuum, the residue is taken
up in 200 ml of water and set at pH 3 with 3N hydrochloric acid.
CA 02243316 1998-07-17
82
Then, it is extracted twice with 200 ml of n-butanol. The
combined butanol phases are evaporated to the dry state in a
vacuum, and the residue is purified by RP-chromatography (RP-
18/mobile solvent: gradient consisting of water/n-
butanol/acetonitrile).
Yield: 30.34 g (78% of theory) of a vitreous solid
Water content: 13.7%
Elementary analysis (relative to anhydrous substance):
Cld: C 37.32 H 4.04 F 36.89 N 7.25
Fnd: C 37.15 H 4.21 F 36.70 N 7.19
b) Gadolinium complex of 10-[2-hydroxy-1H,1H,2H,3H,3H-
perfluorononyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane
g (12.94 mmol) of the title compound of Example 9a) is
dissolved in 100 ml of water/50 ml of ethanol, and 2.34 g (6.47
mmol) of gadolinium oxide is added. It is stirred for 3 hours at
80°C. The solution is filtered and evaporated to the dry state
in a vacuum.
Yield: 13.16 g (quantitative) of a colorless, vitreous
solid
Water content: 9.1%
Elementary analysis (relative to anhydrous substance):
Cld: C 31.11 H 3.05 F 30.75 Gd 16.97 N 6.05
Fnd: C 31.01 H 3.19 F 30.55 Gd 16.71 N 5.88
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83
Esampla to
a) 9H,9H,10H,11H,12H,12H-Perfluoroeicos-10-ene
24.77 g (52.26 mmol) of iH,iH,2H,2H-perfluorodecyl-1-iodide
and 13.71 g (52.26 mmol) of triphenylphosphine are heated to 70°C
in 500 ml of acetone while being stirred. The initially clear
solution quickly turns milky, and the colorless phosphonium salt
is precipitated. The phosphonium salt is filtered off and dried
in a vacuum at 40°C.
Yield: 38.9 g (89% of theory)
This phosphonium salt is used directly in the following
reaction without purification: 5.22 g (46.5 mmol) of potassium-
tert-butylate, 0.20 g (0.75 mmol) of 18-crown 6 and 19.54 g
(42.28 mmol) of 2H,2H-perfluorodecanol are added to the above-
produced phosphonium salt, 38.9 g (46.5 mmol) in 250 ml of
dichloromethane, and it is stirred for 10 hours at room
temperature. It is evaporated to the dry state, and the residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/n-hexane/diethyl ether = 10/20/1).
Yield: 30.3 g (65% of theory relative to the iodide used)
of a colorless, waxy solid
Elementary analysis:
Cld: C 26.92 H 0.68 F 72.40
Fnd: C 26.81 H 0.79 F 72.20
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84
b) 10,11-Epoxy-9H,9H,lOH,i1H,12H,12H-perfluoroeicosane
10.47 g (36.42 mmol) of 3-chloroperoxybenzoic acid (about
60%) is added to 25 g (28.02 mmol) of the title compound of
Example 10a), dissolved in 250 ml of dichloromethane, at 0°C, and
it is stirred overnight at room temperature. 300 ml of 5%
aqueous sodium carbonate solution is added and stirred
thoroughly. The organic phase is separated, dried on magnesium
sulfate and evaporated to the dry state in a vacuum. The residue
is chromatographed on silica gel (mobile solvent: n-
hexane/dichloromethane/diethyl ether = 10/10/1).
Yield: 24.17 g (95% of theory) of a colorless solid
Elementary analysis:
Cld: C 26.45 H 0.67 F 71.12
Fnd: C 26.25 H 0.88 F 71.35
c) 10-[1-(iH,iH-Perfluorononyl)-2-hydroxy-1H,2H,3H,3H-
perfluoroundecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane
7.04 g (0.176 mmol) of sodium hydroxide is added to 7.63 g
(22.02 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane in 35 ml of water. A solution of 20 g
(22.02 mmol) of the title compound of Example 10b), dissolved in
50 ml of n-butanol/40 ml of 2-propanol, is added dropwise to it,
and the solution is heated overnight to 120°C in an autoclave.
It is evaporated to the dry state in a vacuum, the residue is
taken up in 200 ml of water and set at pH 3 with 3N hydrochloric
CA 02243316 1998-07-17
acid. Then, it is extracted twice with 300 ml of n-butanol. The
combined butanol phases are evaporated to the dry state in a
vacuum, and the residue is purified by RP-chromatography (RP-
18/mobile solvent: gradient consisting of water/n-
butanol/acetonitrile).
Yield: 9.79 g (31% of theory) of a colorless, vitreous
solid
Water content: 12.5%
Elementary analysis (relative to anhydrous substance):
Cld: C 32.55 H 2.57 F 51.49 N 4.47
Fnd: C 32.38 H 2.75 F 51.29 N 4.28
d) Gadolinium complex of 10-[1-(1H,1H-perfluorononyl)-2-
hydroxy-1H,2H,3H,3H-perfluoroundecyl]-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
8 g (6.38 mmol) of the title compound of Example 10c) is
dissolved in 50 ml of water/40 ml of ethanol/20 ml of chloroform,
and 1.16 g (3.19 mmol) of gadolinium oxide is added. It is
stirred for 4 hours at 90°C in an autoclave. The solution is
filtered and evaporated to the dry state in a vacuum.
Yield: 9.47 g (quantitative) of a vitreous solid
Water content: 5.2%
Elementary analysis (relative to anhydrous substance):
Cld: C 28.99 H 2.07 F 45.85 Gd 11.16 N 3.98
Fnd: C 28.81 H 2.19 F 45.71 Gd 11.03 N 4.12
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Example ii
a) 7H,7H,8H,9H,lOH,lOH-Perfluorohexadec-8-ene
18.7 g (50 mmol) of lH,iH,2H,2H-perfluorooctyl-1-iodide and
13.11 g (50 mmol) of triphenylphosphine are heated to 70°C in 400
ml of acetone while being stirred. The initially clear solution
quickly turns milky, and the colorless phosphonium salt is
precipitated. The phoaphonium salt is filtered off and dried in
a vacuum at 40°C.
Yield: 28.95 g (91% of theory)
This phosphonium salt is used directly in the following
reaction without purification: 5.05 g (45.5 mmol) of potassium-
tert-butylate, 0.20 g (0.75 mmol) of 18-crown 6 and 14.98 g
(41.36 mmol) of the title compound of Example 8a) are added to
the above-produced phosphonium salt, 28.95 g (45.5 mmol) in 200
ml of dichloromethane, and it is stirred for 10 hours at room
temperature. It is evaporated to the dry state, and the residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/n-hexane/diethyl ether = 10/20/1).
Yield: 19.65 g (61% of theory) of a colorless, waxy solid
Elementary analysis:
Cld: C 22.38 H 0.94 F 76.69
Fnd: C 22.20 H 0.99 F 76.51
b) 8,9-Epoxy-7H,7H,8H,9H,lOH,lOH-perfluorohexadecane
11.03 g (38.35 mmol) of 3-chloroperoxybenzoic acid (about
60%) is added to 19 g (29.5 mmol) of the title compound of
CA 02243316 1998-07-17
87
Example 11a), dissolved in 200 ml of dichloromethane, at 0°C, and
it is stirred overnight at room temperature. 300 ml of 5%
aqueous sodium carbonate solution is added and stirred
thoroughly. The organic phase is separated, dried on magnesium
sulfate and evaporated to the dry state in a vacuum. The residue
is chromatographed on silica gel (mobile solvent: n-
hexane/dichloromethane/diethyl ether = 10/10/1).
Yield: 19.43 g (93% of theory) of a colorless solid
Elementary analysis:
Cld: C 27.14 H 0.85 F 69.75
Fnd: C 27.01 H 0.97 F 69.60
c) 10-[1-(1H,1H-Perfluoroheptyl)-2-hydroxy-1H,2H,3H,3H-
perfluorononyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane
8.59 g (214.6 mmol) of sodium hydroxide is added to 9.3 g
(26.83 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane in 50 ml of water. A solution of 19 g
(26.83 mmol) of the title compound of Example 11b), dissolved in
70 ml of n-butanol/60 ml of 2-propanol, is added dropwise to it,
and the solution is heated overnight to 120°C in an autoclave.
It is evaporated to the dry state in a vacuum, the residue is
taken up in 200 ml of water and set at pH 3 with 3N hydrochloric
acid. Then, it is extracted twice with 300 ml of n-butanol. The
combined butanol phases are evaporated to the dry state in a
vacuum, and the residue is purified by RP-chromatography (RP-
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18/mobile solvent: gradient consisting of water/n-
butanol/acetonitrile).
Yield: 9.4 g (29% of theory) of a vitreous solid
Water content: 12.7%
Elementary analysis (relative to anhydrous substance):
Cld: C 34.17 H 3.06 F 46.84 N 5.31
Fnd: C 33.98 H 3.18 F 46.65 N 5.20
d) Gadolinium complex of 10-[1-(1H,1H-perfluoroheptyl)-2-
hydroxy-1H,2H,3H,3H-perfluorononyl]-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
9 g (8.53 mmol) of the title compound of Example 11c) is
dissolved in 60 ml of water/40 ml of ethanol/30 ml of chloroform,
and 1.54 g (4.27 mmol) of gadolinium oxide is added. It is
stirred for 4 hours at 90°C in an autoclave. The solution is
filtered and evaporated to the dry state in a vacuum.
Yield: 11.45 g (quantitative) of a colorless, vitreous
solid
Water content: 10.2%
Elementary analysis (relative to anhydrous substance):
Cld: C 29.81 H 2.42 F 40.86 Gd 13.01 N 4.63
Fnd: C 29.60 H 2.60 F 40.63 Gd 12.84 N 4.51
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Example i2
a) 7,12-Dioxa-5H,5H,6H,6H,8H,8H,9H,lOH,11H,11H,13H,13H,14H,14H-
perfluorooctadec-9-ene
30 g (91.74 mmol) of lH,iH,2H,2H-perfluorohexyl-1-bromide is
dissolved in 100 ml of toluene, then 3.23 g (36.7 mmol) of cis-
1,4-butene-diol and 1 g (2.95 mmol) of tetrabutylammonium
hydrogen sulfate are added. It is cooled to 0°C, and 16 g (400
mmol) of finely powdered sodium hydroxide is added. Then, it is
stirred for 1 hour at 0°C and overnight at room temperature.
Solid is filtered out, the filtrate is washed twice with 200 ml
of water each, the organic phase is dried on magnesium sulfate
and then evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/n-hexane/acetone = 15/15/1).
Yield: 11.71 g (55% of theory relative to diol) of a waxy
solid
Elementary analysis:
Cld: C 33.12 H 2.43 F 58.93
Fnd: C 33.05 H 2.61 F 58.73
b) 9,10-Epoxy-7,12-dioxa-
5H,5H,6H,6H,8H,8H,9H,lOH,11H,11H,13H,13H,14H,14H-
perfluorooctadecane
7.08 g (24.64 mmol) of 3-chloroperoxybenzoic acid (about
60%) is added to 1l g (18.96 mmol) of the title compound of
Example 12a), dissolved in 100 ml of dichloromethane, at 0°C, and
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it is stirred overnight at room temperature. 150 ml of 5%
aqueous sodium carbonate solution is added and stirred
thoroughly. The organic phase is separated, dried on magnesium
sulfate and evaporated to the dry state in a vacuum. The residue
is chromatographed on silica gel (mobile solvent: n-
hexane/dichloromethane/diethyl ether = 10/10/1).
Yield: 10.74 g (95% of theory) of a colorless solid
Elementary analysis:
Cld: C 32.23 H 2.37 F 57.35
Fnd: C 32.13 H 2.51 F 57.20
c) 10-[1-(2-Oxa-iH,iH,3H,3H,4H,4H-perfluorooctyl)-2-hydroxy-4-
oxa-1H,2H,3H,3H,5H,5H,6H,6H-perfluorodecyl]-1,4,7-
~tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
5.63 g (141 mmol) of sodium hydroxide is added to 6.1 g
(17.61 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane in 40 ml of water. A solution of 10.5 g
(17.61 mmol) of the title compound of Example 12b), dissolved in
50 ml of n-butanol/40 ml of 2-propanol, is added dropwise to it,
and the solution is heated overnight to 120°C in an autoclave.
It is evaporated to the dry state in a vacuum, the residue is
taken up in 200 ml of water and set at pH 3 with 3N hydrochloric
acid. Then, it is extracted twice with 300 ml of n-butanol. The
combined butanol phases are evaporated to the dry state in a
vacuum, and the residue is purified by RP-chromatography (RP-
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18/mobile solvent: gradient consisting of water/n-
butanol/acetonitrile).
Yield: 4.96 g (27% of theory) of a colorless, vitreous
solid
Water content: 9.7%
Elementary analysis (relative to anhydrous substance):
Cld: C 38.27 H 4.17 F 36.32 N 5.95
Fnd: C 38.12 H 4.20 F 36.20 N 5.81
d) Gadolinium complex of 10-[1-(2-oxa-1H,1H,3H,3H,4H,4H-
perfluorooctyl)-2-hydroxy-4-oxa-iH,2H,3H,3H,5H,5H,6H,6H-
perfluorodecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane
4.7 g (5 mmol) of the title compound of Example 12c) is
dissolved in 30 ml of water/30 ml of ethanol/20 ml of chloroform,
and 0.90 g (2.5 mmol) of gadolinium oxide is added. It is
stirred for 3.5 hours at 90°C in an autoclave. The solution is
filtered and evaporated to the dry state in a vacuum.
Yield: 5.89 g (quantitative) of a colorless, vitreous
solid
Water content: 7.1%
Elementary analysis (relative to anhydrous substance):
Cld: C 32.88 H 3.31 F 31.21 Gd 14.35 N 5.11
Fnd: C 32.67 H 3.45 F 31.04 Gd 14.18 N 5.02
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Example 13
a) 1-Phenyl-2,6-dioxa-iH,lH,3H,3H,4H,5H,5H,7H,7H,8H,8H-
perfluorohexa-decan-4-of
1 g (2.94 mmol) of tetrabutylammonium hydrogen sulfate and
15.6 g (390 mmol) of finely powdered sodium hydroxide are added
to 7.14 g (39.2 mmol) of glycerol-1-monobenzylether and 25 g
(43.55 mmol) of iH,lH,2H,2H-perfluorodecyl-1-iodide in 100 ml of
toluene. It is stirred for 24 hours at room temperature. The
organic phase is separated from the solid and washed twice with
5% aqueous hydrochloric acid each. The organic phase is dried on
magnesium sulfate and evaporated to the dry state in a vacuum.
The residue is chromatographed on silica gel (mobile solvent: n-
hexane/acetone = 15/1).
Yield: 19.95 g (81% of theory) of a colorless oil
Elementary analysis:
Cld: C 38.23 H 2.73 F 51.40
Fnd: C 38.10 H 2.89 F 51.25
b) 1-Phenyl-4-(decyloxy)-2,6-dioxa-
iH,iH,3H,3H,4H,5H,5H,7H,7H,8H,8H-perfluorohexadecane
1.12 g (37.24 mmol) of sodium hydride (80% suspension in
mineral oil) is added in portions to 19.5 g (31.03 mmol) of the
title compound of Example 13a), dissolved in 100 ml of
dimethylformamide, and it is stirred for 2 hours at room
temperature. Then, 8.24 g (37.24 mmol) of n-decyl bromide is
added and stirred overnight at 50°C. 150 ml of ice water is
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93
added and extracted twice with 150 ml of ethyl acetate each. The
combined organic phases are washed twice with 150 ml of water
each, dried on magnesium sulfate and evaporated to the dry state.
The residue is chromatographed on silica gel (mobile solvent: n-
hexane/acetone = 20:1).
Yield: 22.66 g (95% of theory) of a waxy solid
Elementary analysis:
Cld: C 46.88 H 4.85 F 42.02
Fnd: C 46.64 H 4.97 F 41.87
c) 2-(Decyloxy)-4-oxa-lH,iH,2H,3H,3H,5H,5H,6H,6H-
perfluorotetradecan-1-of
20 g (26.02 mmol) of the title compound of Example 13b) is
dissolved in 200 ml of isopropanol, and 3 g of palladium catalyst
(10% Pd/C) is added. It is hydrogenated overnight at room
temperature. The catalyst is filtered off, and the filtrate is
evaporated to the dry state in a vacuum.
Yield: 17.65 g (quantitative) of a colorless solid
Elementary analysis:
Cld: C 40.72 H 4.61 F 47.60
Fnd: C 40.55 H 4.76 F 47.43
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d) 1,2-Epoxy-4-oxa-6-(decyloxy)-8-oxa-
1H,1H,2H,3H,3H,5H;5H,6H,7H,7H,9H,9H,lOH,lOH-
perfluorooctadecane
9.25 g (100 mmol) of epichlorohydrin is added in drops to a
mixture of 17 g (25.06 mmol) of the title compound of Example
13c) and 2 g (5.89 mmol) of tetrabutylammonium hydrogen sulfate
in 300 ml of 60% aqueous potassium hydroxide solution/100 ml of
toluene while being stirred vigorously at 10°C, and care is taken
to ensure that the temperature of the reaction solution does not
exceed 20°C. It is allowed to stir for 2 hours at 15°C, and then
4.63 g (50 mmol) of epichlorohydrin is added in drops as
described above. Then, it is stirred overnight at room
temperature. 100 ml of toluene and methyl-tert-butyl ether are
added, and the aqueous phase is separated. The latter is
extracted twice more with 100 ml of toluene each. The organic
phases are combined, dried on magnesium sulfate and concentrated
by evaporation in a vacuum. The residue is chromatographed on
silica gel (mobile solvent: dichloromethane/hexane/acetone =
20/10/1).
Yield: 14.91 g (81% of theory) of a colorless solid
Elementary analysis:
Cld: C 42.51 H 4.80 F 43.97
Fnd: C 42.37 H 4.96 F 43.68
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e) 10-[2-Hydroxy-4,8-dioxa-6-(decyloxy)-
1H,1H,2H,3H,3H,5H,5H,6H,7H,7H,9H,9H,lOH,lOH-
perfluorooctadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododeoane
6.11 g (152.8 mmol) of sodium hydroxide is added to 6.6 g
(19.06 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane in 60 ml of water. A solution of 14 g
(19.06 mmol) of the title compound of Example 13d), dissolved in
80 ml of n-butanol/40 ml of 2-propanol, is added dropwise to it,
and the solution is heated overnight to 80°C in an autoclave. It
is evaporated to the dry state in a vacuum, the residue is taken
up in 200 ml of water, and it is sat at pH 3 with 3N hydrochloric
acid. Then, it is extracted twice with 300 ml of n-butanol. The
combined butanol phases are evaporated to the dry state in a
vacuum, and the residue is purified by RP-chromatography (RP-
18/mobile solvent: gradient consisting of water/n-
butanol/acetonitrile).
Yield: 17.88 g (76% of theory) of a vitreous solid
Water content: 12.5%
Elementary analysis (relative to anhydrous substance):
Cld: C 44.49 H 5.60 F 29.91 N 5.19
Fnd: C 44.31 H 5.75 F 29.70 N 5.03
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f) Gadolinium complex of 10-[2-hydroxy-4,8-dioxa-6-(decyloxy)-
1H,1H,2H,3H,3H,5H,5H,6H,7H,7H,9H,9H,lOH,lOH-
perfluorooctadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane
g (9.26 mmol) of the title compound of Example 13e) is
dissolved in 30 ml of water/100 ml of ethanol/30 ml of
chloroform, and 1.68 g (4.63 mmol) of gadolinium oxide is added.
It is stirred for 3.5 hours at 90°C in an autoclave. The
solution is filtered and evaporated to the dry state in a vacuum.
Yield: 12.39 g (quantitative) of a colorless, vitreous
solid
Water content: 7.8%
Elementary analysis (relative to anhydrous substance):
Cld: C 38.93 H 4.66 F 26.17 Gd 12.74 N 4.54
Fnd: C 38.71 H 4.82 F 26.01 Gd 12.55 N 4.38
Example 14
a) 1-Phenyl-2-oxa-4,4,4-tris(2-oxa-1H,1H,3H,3H,4H,4H-
perfluorodecyl)-butane
2 g (5.89 mmol) of tetrabutylammonium hydrogen sulfate and
22.48 g (562 mmol) of finely powdered sodium hydroxide are added
to 4.24 g (18.74 mmol) of pentaerythritol monobenzyl ether and 40
g (93.7 mmol) of iH,lH,2H,2H-perfluorooctyl-1-bromide in 150 ml
of toluene. It is stirred for 24 hours at room temperature. The
organic phase is separated from the solid and washed twice with
5% aqueous hydrochloric acid each. The organic phase is dried on
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magnesium sulfate and evaporated to the dry state in a vacuum.
The residue is chromatographed on silica gel (mobile solvent: n-
hexane/acetone = 25/1).
Yield: 14.45 g (61% of theory relative to the benzyl
ether) of a colorless, waxy solid
Elementary analysis:
Cld: C 34.19 H 2.15 F 58.59
Fnd: C 34.02 H 2.31 F 58.41
b) 2,2,2-Tris(2-oxa-IH,iH,3H,3H,4H,4H-perfluorodecyl)-ethan-
1-0l
14 g (11.07 mmol) of the title compound of Example 14a) is
dissolved in 100 ml of isopropanol/100 ml of tetrahydrofuran, and
3 g of palladium catalyst (10% Pd/C) is added. It is
hydrogenated overnight at room temperature. The catalyst is
filtered off, and the filtrate is evaporated to the dry state in
a vacuum.
Yield: 13 g (quantitative) of a colorless solid
Elementary analysis:
Cld: C 29.66 H 1.80 F 63.09
Fnd: C 29.45 H 1.97 F 62.91
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c) 1,2-Epoxy-4-oxa-6,6,6-tris(2-oxa-1H,1H,3H,3H,4H,4H-
perfluorodecyl)-hexane
3.94 g (42.57 mmol) of epichlorohydrin is added in drops to
a mixture of 12.5 g (10.64 mmol) of the title compound of Example
14b) and 1 g (2.95 mmol) of tetrabutylammonium hydrogen sulfate
in 150 ml of 60% aqueous potassium hydroxide solution/50 ml of
toluene while being stirred vigorously at 10°C, and care is taken
to ensure that the temperature of the reaction solution does not
exceed 20°C. It is allowed to stir for 2 hours at 15°C, and then
1.97 g (21.29 mmol) of epichlorohydrin is added in drops as
described above. Then, it is stirred overnight at room
temperature. 100 ml of toluene and 100 ml of methyl-tert-butyl
ether are added, and the aqueous phase is separated. The latter
is extracted twice more with 50 ml of toluene each. The organic
phases are combined, dried on magnesium sulfate and concentrated
by evaporation in a vacuum. The residue is chromatographed on
silica gel (mobile solvent: dichloromethane/hexane/acetone =
20/10/1).
Yield: 8.12 g (62% of theory) of a colorless solid
Elementary analysis:
Cld: C 31.24 H 2.05 F 60.22
Fnd: C 31.09 H 2.19 F 60.10
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d) 10-[2-Hydroxy-4-oxa-6,6,6-tris(2-oxa-lH,iH,3H,3H,4H,4H-
perfluorodecyl)-hexyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane
2.08 g (52 mmol) of sodium hydroxide is added to 2.25 g
(6.50 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane in 30 ml of water. A solution of 8.0 g
(6.50 mmol) of the title compound of Example 14c), dissolved in
50 ml of n-butanol/30 ml of 2-propanol, is added dropwise to it,
and the solution is heated overnight to 100°C in an autoclave.
It is evaporated to the dry state in a vacuum, the residue is
taken up in 200 ml of water and set at pH 3 with 3N hydrochloric
acid. Then, it is extracted twice with 100 ml of n-butanol. The
combined butanol phases are evaporated to the dry state in a
vacuum, and the residue is purified by RP-chromatography (RP-
18/mobile solvent: gradient consisting of water/n-
butanol/acetonitrile).
Yield: 7.79 g (67% of theory) of a colorless, vitreous
solid
Water content: 11.9%
Elementary analysis (relative to anhydrous substance):
Cld: C 35.06 H 3.20 F 47.02 N 3.56
Fnd: C 34.90 H 3.38 F 46.86 N 3.47
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e) Gadolinium complex of 10-[2-hydroxy-4-oxa-6,6,6-tris(2-oxa-
iH,iH,3H,3H,4H,4H-perfluorodecyl)-hexyl]-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
7 g (4.44 mmol) of the title compound of Example 14d) is
dissolved in 30 ml of water/50 ml of ethanol/50 ml of chloroform,
and 0.80 g (2.22 mmol) of gadolinium oxide is added. It is
stirred for 5 hours at 90°C in an autoclave. The solution is
filtered and evaporated to the dry state in a vacuum.
Yield: 8.34 g (quantitative) of a colorless, vitreous
solid
Water content: 8.1%
Elementary analysis (relative to anhydrous substance):
Cld: C 31.94 H 2.74 F 42.83 Gd 9.09 N 3.24
Fnd: C 31.74 H 2.91 F 42.67 Gd 8.85 N 3.15
Example 15
a) 1,7-Bis[acetyl-(2-(N-ethyl-N-perfluorooctylsulfonylamino)]-
1,4,7-triazaheptane
20 g (34.17 mmol) of the title compound of Example 1b) and
4.33 g (37.59 mmol) of N-hydroxysuccinimide are dissolved in 150
ml of dimethylformamide. 7.76 g (37.59 mmol) of
dicyclohexylcarbodiimide is added at 0°C and stirred for 3 hours
at room temperature. Dicyclohexylurea is filtered out, and the
filtrate is added in drops to a solution of 1.76 g (17.09 mmol)
of diethylenetriamine mnd 13.83 g (136.7 mmol) of triethylamine
in 200 ml of dimethylformamide at room temperature. It is
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stirred overnight at room temperature. It is evaporated to the
dry state in a vacuum, and the residue is taken up in 200 ml of
5% aqueous soda solution. It is extracted twice with 150 ml of
dichloromethane each, the combined organic phases are dried on
magnesium sulfate and evaporated to the dry state in a vacuum.
The residue is chromatographed on silica gel (mobile solvent:
dichloromethane/2-propanol = 20/1).
Yield: 16.5 g (78% of theory) of a waxy solid
Elementary analysis:
Cld: C 27.17 H 2.04 F 52.19 N 5.66 S 5.18
Fnd: C 27.03 H 2.17 F 52.04 N 5.49 S 5.07
b) 4-(3-Carboxy-propanoyl)-1,7-bis-{acetyl-[2-(N-ethyl-N-
perfluorooctylsulfonylamino)]}-1,4,7-triazaheptane
3.92 g (38.78 mmol) of triethylamine is added to 16 g (12.93
mmol) of the title compound of Example 15a) in 100 ml of
methylene chloride, and the solution is cooled to 0°C. Then,
2.59 g (25.86 mmol) of succinic acid anhydride is added and
stirred for 3 hours at 0°C, overnight at room temperature. 200
ml of 5% aqueous hydrochloric acid is added and shaken well. The
organic phase is separated and dried on magnesium sulfate. It is
evaporated to the dry state in a vacuum, and the residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/2-propanol = 15/1).
Yield: 15.74 g (91% of theory) of a colorless solid
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Elementary analysis:
Cld: C 28.73 H 2.19 F 48.29 N 5.24 S 4.79
Fnd: C 28.58 H 2.40 F 48.17 N 5.17 S 4.65
c) 10-[7-Hydroxy-5-aza-4-oxo-octanoic acid-N,N-bis(3-aza-4-oxo-
6-aza-6-(perfluorooctylsulfonyl)-octyl)-amide]-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
15 g (11.21 mmol) of the title compound of Example 15b) and
1.42 g (12.33 mmol) of N-hydroxysuccinimide are dissolved in a
mixture of 80 ml of dimethylformamide/30 ml of chloroform. 2.54
g (12.33 mmol) of dicyclohexylcarbodiimide is added at 0°C and
stirred for 1 hour at 0°C, then for 3 hours at room temperature.
It is cooled again to 0°C, and 4.05 g (40 mol) of
triethylamine/50 ml of 2-propanol is added. Then, 7.07 g (12.33
mmol) of the gadolinium complex of 10-[2-hydroxy-3-amino-propyl]-
1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane,
dissolved in 30 ml of water, is added and stirred.for 3 hours at
room temperature. It is evaporated to the dry state, the residue
is taken up in a mixture of 100 ml of methanol/50 ml of
chloroform, and dicyclohexylurea is filtered out. The filtrate
is evaporated to the dry state and purified by RP-chromatography
(RP-18/mobile solvent: gradient consisting of water/n-
propanol/acetonitrile).
Yield: 17.76 g (78% of theory) of a colorless, vitreous
solid
Water content: 6.8%
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103
Elementary analysis (relative to anhydrous substance):
Cld: C 31.08 H 3.03 F 34.12 Gd 8.31 N 7.40 S 3.39
Fnd: C 30.89 H 3.15 F 34.01 Gd 8.14 N 7.25 S 3.24
B:alnple 16
Gadolinium complex of 1,4,7-tris(carboxylatomethyl)-10-(2-
hydroxy-19,19,20,20,21,21,22,22,23,23,24,24,25,25,26,26,26-
heptadecafluoro-4,7,10,13,16-penta-oxa-hexacosane)-1,4,7,10-
tetraazacyclododecane
a) 16,16,17,17,18,18,19,19,20,20,21,21,22,22,22-
Heptadecafluoro-3,6,9,12-tetra-oxa-docosan-1-of
A mixture of 20 g (32.35 mmol) of 1-p-toluenesulfonyloxy-
1H,1H,2H,2H-perfluorodecane [see Example 7a], 1 g of
tetrabutylammonium hydrogen sulfate, 62.83 g (323.5 mmol) of
tetraethylene glycol, 300 ml of dichloromethane and 100 ml of 50%
sodium hydroxide solution is stirred intensively at about 5°C for
24 hours. It is then diluted with 200 ml of dichloromethane, the
phases are separated, and the dichloromethane phase is washed
with water. The organic phase is dried on magnesium sulfate and
concentrated by evaporation in a vacuum. 18.5 g of the desired
title compound is obtained as a light yellow oil.
b) 1,2-Epoxy-19,19,20,20,21,21,22,22,23,23,24,24,25,25,
26,26,26-heptadecafluoro-4,7,10,13,16-penta-oxa-hexacosane
A mixture of 17 g (26.5 mmol) of 16,16,17,17,18,18,19,19,
20,20,21,21,22,22,22-heptadecafluoro-3,6,9,12-tetra-oxa-docosan-
1-0l, 0.5 g of tetrabutylammonium hydrogen sulfate, 2.94 g of
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epichlorohydrin, 200 ml of dichloromethane and 50 ml of 50%
sodium hydroxide solution is stirred intensively at room
temperature for 8 hours. The phases are separated, the aqueous
phase is shaken with 100 ml of dichloromethane, the organic
phases are combined, shaken With 50 ml of water, dried on
magnesium sulfate and concentrated by evaporation in a vacuum.
The residue is chromatographed on silica gel with hexane/5-50%
ethyl acetate, and 12.92 g of the title compound is obtained as
an oil.
Elementary analysis:
Cld: C 36.22 H 3.62 F 46.38
Fnd: C 36.00 H 3.78 F 46.20
c) 1,4,7-Tris(carboxylatomethyl)-10-(2-hydroxy-
19,19,20,20,21,21,22,22,23,23,24,24,25,25,26,26,26-
heptadecafluoro-4,7,10,13,16-penta-oxa-hexacosane)-1,4,7,10-
tetraazacyclododecane
A solution of 12.05 g (17.3 mmol) of 1,2-epoxy-
19,19,20,20,21,21,22,22,23,23,24,24,25,25,26,26,26-
heptadecafluoro-4,7,10,13,16-penta-oxa-hexacosane in 50 ml of
tetrahydrofuran is added to a solution of 6 g (17.3 mmol) of
1,4,7-(triscarboxylatomethyl)-1,4,7,10-tetraazacyclododecane and
4 g of sodium hydroxide in 30 ml of water. It is stirred
overnight at 70°C, then largely concentrated by evaporation in a
vacuum, the residue is taken up in 150 ml of water and set at pH
3 with 6N hydrochloric acid and extracted several times with n-
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butanol. The combined extracts are concentrated by evaporation
in a vacuum, and the residue is purified by chromatography on RP-
18 with a gradient consisting of water/n-butanol/acetonitrile.
13.71 g of the title compound is obtained as a yellow viscous
oil.
Elementary analysis:
Cld: C 40.31 H 4.93 F 30.97 N 5.37
Fnd: C 40.08 H 5.21 F 30.77 N 5.29
d) Gadolinium complex of 1,4,7-tris(carboxylatomethyl)-l0-(2-
hydroxy-19,19,20,20,21,21,22,22,23,23,24,24,25,25,26,26,26-
heptadecafluoro-4,7,10,13,16-penta-oxa-hexacosane)-1,4,7,10-
tetraazacyclododecane
A mixture of 5 g (4.79 mmol) of 1,4,7-tris(carboxylato-
methyl)-10-(2-hydroxy-19,19,20,20,21,21,22,22,23,23,
24,24,25,25,26,26,26-heptadecafluoro-4,7,10,13,16-penta-oxa-
hexacosane)-1,4,7,10-tetraazacyclododecane, 50 ml of water and 30
ml of ethanol is mixed with 869 mg (2.397 mmol) of gadolinium
oxide, and it is refluxed for 5 hours. The hot solution is
filtered and concentrated by evaporation in a vacuum. 5.60 g of
the title compound is obtained as a vitreous, solid substance
with a water content of 4.1%.
Elementary analysis (relative to anhydrous substance):
Cld: C 35.12 H 4.04 F 26.98 Gd 13.14 N 4.68
Fnd: C 34.90 H 4.38 F 26.70 Gd 13.10 N 4.62
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Exampl~ 17
Gadolinium complex of 1,4,7-tris(carboxylatomethyl)-10-(4-aza-2-
hydroxy-26,26,26,25,25,24,24,23,23,22,22,21,21,20,20,19,19-
heptadecafluoro-5-oxo-16-thia-hexacosyl)-1,4,7,10-
tetraazacyclododecane
a) 22,22,22,21,21,20,20,19,19,18,18,17,17,16,16,15,15-
Heptadecafluoro-12-thia-docosanoic acid
A solution of 10 g (37.71 mmol) of il-bromoundecanoic acid
in 150 ml of dichloromethane is mixed with 11.43 g of
triethylamine and 18.11 g (37.71 mmol) of iH,iH,2H,2H-
perfluorodecylmercaptan, and it is stirred overnight at room
temperature. The solution is extracted several times with 2N
hydrochloric acid, washed with common salt solution, dried on
magnesium sulfate and concentrated by evaporation in a vacuum.
21.5 g of the title compound is obtained as a yellow oil.
Elementary analysis:
Cld: C 37.96 H 3.79 F 48.61 S 4.83
Fnd: C 38.30 H 4.01 F 48.40 S 5.20
b) Gadolinium complex of 1,4,7-tris(carboxylatomethyl)-10-(4-
aza-2-hydroxy-26,26,26,25,25,24,24,23,23,22,22,
21,21,20,20,19,19-heptadecafluoro-5-oxo-16-thia-hexacosyl)-
1,4,7,10-tetraazacyclododecane
g (7.52 mmol) of the title compound of Example 17a) and
0.95 g of N-hydroxysuccinimide are dissolved in a mixture of 25
ml of dimethylformamide and 15 ml of chloroform. 1.71 g of
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dicyclohexylcarbodiimide is added at 0°C and stirred for 1 hour
at 0°C, then for 3 hours at room temperature. It is then cooled
again to 0°C and mixed with 3 ml of triethylamine and 20 ml of n-
propanol. Then, 4.75 g (8.27 mmol) of the gadolinium complex of
10-(3-amino-2-hydroxy-propyl)-1,4,7-tris(carboxylatomethyl)-
1,4,7,10-tetraazacyclododecane, dissolved in 25 ml of water, is
added and stirred for 3 hours at 20°C. It is evaporated to the
dry state, the residue is taken up in a mixture of 55 ml of
methanol and 20 ml of chloroform, and dicyclohexylurea is
filtered out. The filtrate is evaporated to the dry state and
purified by chromatogrmphy on RP-18 with a gradient consisting of
water/n-propanol/acetonitrile. 6.15 g of the title compound is
obtained as a vitreous solid, with a water content of 2.3%.
Elementary analysis (relative to anhydrous substance):
Cld: C 37.41 H 4.38 F 26.47 Gd 12.89 N 5.74 S 2.63
Fnd: C 37.08 H 4.60 F 26.30 Gd 12.68 N 5.91 S 2.49
Example i8
Gadolinium complex of 1,4,7-tris(carboxylatomethyl)-10-[1-(1,2-
dihydroxyethyl)3-oxa-6,6,7,7,8,8,9,9,10,10,11,11,11-
tridecafluoro]undecane-1,4,7,10-tetraazacyclododecane
a) 1-p-Toluenesulfonyloxy-iH,iH,2H,2H-perfluorooctane
20 ml of pyridine is added to a solution of 25 g (68.7 mmol)
of iH,iH,2H,2H-perfluorooctan-1-of in 300 ml of dichloromethane
at 0°C, and 13.49 g (70.76 mmol) of p-toluenesulfonic acid
chloride is added in portions while being stirred. It is stirred
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for 3 more hours at 0°C, and the dichloromethane is drawn off at
room temperature in a vacuum. The remaining pyridine solution is
mixed with ice water, whereby the desired product precipitates.
The residue is decanted and dissolved in dichloromethane, the
solution is washed with water, dried on magnesium sulfate and
concentrated by evaporation in a vacuum. The residue is purified
by chromatography on silica gel with hexane/5-40% ethyl acetate.
29.2 g of the title compound is obtained as a viscous foam.
Elementary analysis:
Cld: C 34.76 H 2.14 F 47.65 S 6.19
Fnd: C 34.98 H 2.38 F 47.39 S 6.42
b) 1,4,7-Tris(benzyloxycarbonyl)-10-[1-(2,2-dimethyl-1,3-
dloXOlari-4-yl)-6,6,7,7,8,8,9,9,10,10,11,11,11-trldecafluor0-
3-oxa]-undecane-1,4,7,10-tetraazacyclododecane
20 ml of 50% sodium hydroxide solution, 0.5 g of
tetrabutylammonium hydrogen sulfate and 5.18 g (10 mmol) of 1-p-
toluenesulfonyloxy-iH,iH,2H,2H-perfluorooctane [see Example 18a)]
are added in succession to 7.33 g (10 mmol) of 1,4,7-
tris(benzyloxycarbonyl)-10-[2-hydroxy-1-(2,2-dimethyl-1,3-
dioxolan-4-yl)]-ethyl-1,4,7,10-tetraazacyclododecane [J. Mag.
Res. Imag. 5_: 7-10, (1955)], dissolved in 100 ml of
dichloromethane, and the mixture is stirred intensively overnight
at room temperature. The phases are separated, the organic phase
is washed several times with water, dried on magnesium sulfate
and concentrated by evaporation in a vacuum. The residue is
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purified by chromatography on silica gel with dichloromethane/1-
10% ethanol. 8.02 g of the title compound is obtained as a
viscous oil.
Elementary analysis:
Cld: C 53.01 H 5.02 F 23.19 N 5.26
Fnd: C 53.30 H 5.39 F 23.01 N 5.40
c) 1-[1-(2,2-Dimethyl-1,3-dioxolan-4-yl)-
6,6,7,7,8,8,9,9,10,10,11,11,11-tridecafluoro-3-oxa]-
undecane-1,4,7,10-tetraazacyclododecane
A solution of 7 g (6.57 mmol) of 1,4,7-
tris(benzyloxycarbonyl)-10-[1-(2,2-dimethyl-1,3-dioxolan-4-yl)-
6,6,7,7,8,8,9,9,10,10,11,11,11-tridecafluoro-3-oxa]-undecane-
1,4,7,10-tetraazacyclododecane in 100 ml of isopropyl alcohol is
mixed with 0.7 g of palladium on carbon (10%), and it is shaken
for 3 hours under hydrogen atmosphere. Catalyst is filtered out,
and the solution is concentrated by evaporation in a vacuum.
4.20 g of the title compound is obtained as a vitreous foam.
Elementary analysis:
Cld: C 41.70 H 5.32 F 37.28 N 8.46
Fnd: C 41.61 H 5.57 F 37.10 N 8.59
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d) 1,4,7-Tris(carboxylatomethyl)-10-[1-(1,2-dihydroxy-ethyl)-3-
oxa-6,6,7,7,8,8,9,9,10,10~,11,11,11-tridecafluoro]undecane-
1,4,7,10-tetraazacyclododecane
3.36 g (24.15 mmol) of bromoacetic acid in 50 ml of water is
dissolved and mixed with 6N sodium hydroxide solution until pH 7
is reached. A solution of 4 g (6.04 mmol) of 1-[1-(2,2-dimethyl-
1,3-dioxolan-4-yl)-6,6,7,7,8,8,9,9,10,10,11,11,11-tridecafluoro-
3-oxa]-undecane-1,4,7,10-tetraazacyclododecane, dissolved in 20
ml of isopropyl alcohol, and enough 6N sodium hydroxide solution
are added in drops at 40°C while simultaneously being stirred so
that the pH is kept at 9-10. Then, it is mixed with
semiconcentrated hydrochloric acid up to pH 1 and stirred for
another 3 hours at 60°C. It is cooled to room temperature, and
the solution is extracted several times with n-butanol. The
organic extract is concentrated by evaporation, and the residue
is purified by chromatography on RP-18 with a gradient consisting
of water/n-butanol/acetonitrile. 3.85 g of the title compound is
obtained as a yellow oil with a water content of 3.9%.
Elementary analysis (relative to anhydrous substance):
Cld: C 39.20 H 4.68 F 31.00 N 7.03
Fnd: C 39.08 H 4.98 F 30.72 N 7.29
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e) Gadolinium complex of 1,4,7-tris(carboxylatomethyl)-10-[1-
(1,2-dihydroxy-ethyl)-3-oxa-6,6,7,7,8,8,9,9,10,10,11,11,11-
tridecafluoro]unde~cane-1,4,7,10-tetraazacyclododecane
A mixture of 1.59 g (2 mmol) of 1,4,7-
tris(carboxylatomethyl)-10-[1-(1,2-dihydroxy-ethyl)-3-oxa-
6,6,7,7,8,8,9,9,10,10,11,11,11-tridecafluoro]undecane-1,4,7,10-
tetraazacyclododecane, 25 ml of water and 15 ml of ethanol is
mixed with 363 mg (1 mmol) of gadolinium oxide, and it is
refluxed for 5 hours. The hot solution is filtered, concentrated
by evaporation in a vacuum, and 1.85 g of the title compound is
obtained as a vitreous, solid substance with a water content of
4.2%.
Elementary analysis (relative to anhydrous substance):
Cld: C 32.84 H 3.60 F 25.98 Gd 16.54 N 5.89
Fnd: C 32.53 H 3.71 F 25.72 Gd 16.39 N 5.93
Example 19
Gadolinium complex of 1,4,7-tris(carboxylatomethyl)-10-{2-
hydroxy-4-oxa-4-[4-(2H,2H,3H,3H-1-oxa-perfluoroundec-1-yl)]-
phenyl}-but-1-yl-1,4,7,10-tetraazacyclododecane
a) 1-Hydroxy-4-(2H,2H,3H,3H-1-oxa-perfluoroundec-1-yl)-benzene
g (45.41 mmol) of hydroquinone is mixed with 100 ml of
acetone and mixed while being stirred in succession with 13.8 g
of potassium carbonate and 14.04 g (22.7 mmol) of 1-p-
toluenesulfonyloxy-lH,iH,2H,2H-perfluorodecane [see Example 7a)].
It is refluxed for 6 hours, than largely concentrated by
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evaporation in a vacuum, diluted with 200 ml of water, set at pH
3 with citric acid and extracted several times with
dichloromethane. The organic extract is dried on magnesium
sulfate and concentrated by evaporation in a vacuum. The residue
is purified by chromatography on silica gel with hexane/5-30%
ethyl acetate. 8.20 g of the desired title compound is obtained
as a viscous oil.
Elementary analysis:
Cld: C 34.55 H 1.63 F 58.07
Fnd: C 34.31 H 1.79 F 58.01
b) 1-(3,4-Epoxy-1-oxa-but-1-yl)-4-(2H,2H,3H,3H-1-oxa-
perfluoroundec-1-yl)-benzene
A mixture of 8 g (14.38 mmol) of 1-hydroxy-4-(2H,2H,3H,3H-1-
oxa-perfluoroundec-1-yl)-benzene, 0.4 g of tetrabutylammonium
hydrogen sulfate, 1.60 g (17.26 mmol) of epichlorohydrin, 150 ml
of dichloromethane and 30 ml of 50% sodium hydroxide solution is
stirred intensively for 30 minutes in an ice bath, then for 5
hours at room temperature. The phases are separated, the organic
phase is washed with water, dried on magnesium sulfate and
concentrated by evaporation in a vacuum. The residue is purified
by chromatography on silica gel with hexane/5-30% ethyl acetate,
and 6.60 g of the title compound is obtained as a viscous oil.
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Elementary analysis:
Cld: C 37.27 H 2.41 F 52.75
Fnd: C 37.10 H 2.66 F 52.80
c) 1,4,7-Tris(carboxylatomethyl)-10-{2-hydroxy-4-oxa-4-[4-
(2H,2H,3H,3H-1-oxa-perfluoroundec-1-yl)]-phenyl}-but-1-yl-
1,4,7,10-tetraazacyclododecane
A solution of 6.12 g (10 mmol) of 1-(3,4-epoxy-1-oxa-but-1-
yl)-4-(2H,2H,3H,3H-1-oxa-perfluoroundec-1-yl)-benzene in 25 ml of
tetrahydrofuran is added to a solution of 3.46 g (10 mmol) of
1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclvdodecane and
2.5 g of sodium hydroxide in 25 ml of water, and it is refluxed
for 24 hours, then largely concentrated by evaporation in a
vacuum, the residue is dissolved in 100 ml of water, set at pH 3
with 6N hydrochloric acid and extracted several times with n-
butanol. The combined extracts are concentrated by evaporation
in a vacuum. The residue is purified by chromatography on RP-18
with a gradient consisting of water/n-butanol/acetonitrile. 6.71
g of the title compound is obtained as a viscous oil.
Elementary analysis:
Cld: C 41.35 H 4.10 F 33.69 N 5.84
Fnd: C 41.58 H 4.38 F 33.50 N 5.91
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d) Gadolinium complex of 1,4,7-tris(carboxylatomethyl)-10-{2-
hydroxy-4-oxa-4-[4-(2H,2H,3H,3H-1-oxa-perfluoroundec-1-yl)]-
phenyl}-but-1-yl-1,4,7,10-tetraazacyclododecane
A mixture of 4.79 g (5 mmol) of 1,4,7-
tris(carboxylatomethyl)-10-{2-hydroxy-4-oxa-4-[4-(2H,2H,3H,3H-1-
oxa-perfluoroundec-1-yl)]-phenyl}-but-1-yl-1,4,7,10-
tetraazacyclododecane, 50 ml of water and 30 ml of ethanol is
mixed with 906 mg (2.5 mmol) of gadolinium oxide and refluxed for
hours. The hot solution is filtered and concentrated by
evaporation in a vacuum. 5.50 g of the title compound is
obtained as a vitreous solid substance with a water content of
4.9%.
Elementary analysis (relative to anhydrous substance):
Cld: C 35.62 H 3.26 F 29.02 Gd 14.13 N 5.03
Fnd: C 35.40 H 3.50 F 28.81 Gd 14.01 N 5.18
Example 20
Gadolinium complex, disodium salt of 3,9-bis(carboxymethyl)-6-
[(1-carboxy)-1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl]-3,6,9-
triazaundecanedioic acid
a) N-t-Butoxycarbonyl-serine-(1H,1H,2H,2H-perfluorodecyl)-
ether-benzyl ester
300 mg (10 mmol) of sodium hydride (80% in oil) is added in
portions to a solution of 2.953 g (10 mmol) of N-t-
butyloxycarbonyl-serine-benzyl ester (Bachem commercially
available products) in 30 ml of dry dimethylformamide. After
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dissolving is completed, it is mixed with 6.072 g (10 mmol) of
the tosylate produced under 7a). It is stirred for 12 hours at
room temperature. Then, it is poured into 500 ml of ice water,
the product is taken up in dichloromethane, the organic solution
is washed with water, dried on sodium sulfate and evaporated to
the dry state. The residue is purified by chromatography on
silica gel. A mixture of dichloronethane with increasing
addition of methanol is used as eluant.
The title compound is obtained as a syrup.
Yield: 5.902 g (79.6% of theory)
Elementary analysis:
Cld: C 40.50 H 3.26 F 43.56 N 1.89
Fnd: C 40.64 H 3.37 F 43.49 N 1.83
b) Serine-(iH,iH,2H,2H-perfluorodecyl)-ether-benzyl ester (as a
salt of trifluoroacetic acid
7.414 g (10 mmol) of the N-protected compound that is
produced under 20a) is dissolved in 50 ml of a mixture of
trifluoroacetic acid and dichloromethane at a 2:1 ratio, and it
is stirred overnight at room temperature. It is evaporated to
the dry state, and the remainder of the trifluoroacetic acid is
removed by codistillation with ethanol. The title compound is
isolated as a salt of trifluoroacetic acid.
Yield: 7.418 g (98.2% of theory)
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Elementary analysis:
Cld: C 34.98 H 2.27 F 50.30 N 1.85
Fnd: C 34.89 H 2.31 F 50.39 N 1.80
c) 3,9-Bis(t-butoxycarbonylmethyl)-6-[(1-benzyloxycarbonyl)-
1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-3,6,9-
triazaundecanedioic acid-di(t-butyl)-ester
3.777 g (5 mmol) of the amine-trifluoroacetate that is
produced under 20b) and 3.523 g (10 mmol) of N,N-bis(t-
butyloxycarbonylmethyl)-2-(bromoethyl)-amine are added to a
mixture of 10 ml of acetonitrile and 20 ml of phosphate buffer of
pH 8.0, and it is stirred intensively at room temperature for 2
hours. Then, the buffer phase is separated, extracted with 10 ml
of acetonitrile, and the latter is added to the organic phase.
After 20 ml of fresh buffer is added, it is stirred for 20 more
hours at room temperature. The organic phase is separated,
concentrated by evaporation, and the residue is dispersed between
100 ml of phosphate buffer (pH 8.0) and 100 ml of ethyl acetate.
The organic phase is washed with saturated common salt solution,
dried on sodium sulfate and concentrated by evaporation. The
title compound is purified by chromatography on silica gel.
Dichloromethane is used as eluant with increasing addition of
methanol. The title compound is obtained as a glass-like solid.
Yield: 3.162 g (53.4% of theory)
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Elementary analysis:
Cld: C 48.69 H 5.62 F 27.28 N 3.55
Fnd: C 48.82 H 5.72 F 27.37 N 3.50
d) 3,9-Bis(carboxymethyl)-6-[(1-carboxy)-iH,2H,2H,4H,4H,5H,5H-
3-oxa-perfluorotridecyl]-3,6,9-triazaundecanedioic acid
5.920 g (5 mmol) of the compound that is produced under 20c)
is added to a mixture of 25 ml of trifluoroacetic
acid/dichloromethane at a 2:1 ratio. It is allowed to stir
overnight at room temperature, then evaporated to the dry state,
the residue is taken up in 100 ml of 3N hydrochloric acid,
refluxed for 3 hours, then evaporated to the dry state in a
vacuum and taken up in 160 ml of a mixture of water, ethanol and
chloroform (10:5:1). The solution is set at a constant pH (about
3) by adding ion exchanger IRA 67 (OH' form). It is quickly
suctioned out, concentrated by evaporation, and the title
compound is obtained as a vitreous solid.
Yield: 3.080 g (71.3% of theory)
Water content: 11.3%
Elementary analysis (relative to anhydrous substance):
Cld: C 34.53 H 3.25 F 37.15 N 4.83
Fnd: C 34.41 H 3.32 F 37.29 N 4.90
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e) Gadolinium complex, disodium salt of 3,9-bis(carboxymethyl)-
6-[(1-carboxy)-iH,2H,2H,4H,4H,5H,5H-3-oxa-
perfluorotridecyl]-3,6,9-triazaundecanedioic acid
2.941 g (3.0 mmol, relative to 11.3% water content) of the
acid that is produced under 20d) is added to a mixture of 60 ml
of distilled water and 30 ml of ethanol. 543.8 mg (1.5 mmol) of
gadolinium oxide is added in portions while being stirred and
heated to 50°C. After addition is completed, it is stirred until
dissolved. The pH of the solution is then set at 7.2 by adding
sodium hydroxide solution. The solution is then concentrated by
evaporation, whereby strong foaming can be observed. The residue
is codistilled with distilled water. The title compound is
obtained as a vitreous solid.
Yield: 3.489 g (quantitative)
Water content: 8.2$
Elementary analysis (relative to anhydrous substance):
Cld: C 28.12 H 2.17 F 30.25 Gd 14.73 N 3.94 Na 4.31
Fnd: C 28.25 H 2.26 F 30.40 Gd 14.85 N 3.99 Na 4.38
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E7cample 21
Gadolinium complex, monosodium salt of 3,6,9-tris(carboxymethyl)-
3,6,9-triazaundecanedioic acid-mono-N-{ethyl-2-amino-
[carbonylmethyl-amino-(N-ethyl-N-perfluorooctylsulfonyl)]}-amide
a) 3,6,9-Tris(carboxylatomethyl)-3,6,9-triazaundecanedioic
acid-mono-N-{ethyl-2-amino-[carbonylmethyl-amino-(N-ethyl-N-
perfluorooctylsulfonyl)]}-amide
17.87 g (50 mmol) of diethylenetriaminepentaacetic acid-bis-
anhydride is suspended in 200 ml of a mixture of
dimethylformamide and dichloromethane at a 4:1 ratio and mixed in
portions with the mixture of 3.137 g (5 mmol) of [N-(2-
aminoethyl)-N-perfluorooctylsulfonyl]-aminoacetic acid-N-(2-
aminoethyl)-amide and 6.50 g (64.2 mmol) of triethylamine while
being stirred vigorously. It is allowed to stir for 5 more
hours, evaporated to the dry state, mixed with 300 ml of ice
water, and the pH of the batch is set at about 3 with 3N
hydrochloric acid. It is extracted twice with 200 ml of n-
butanol each, the organic solutions are combined and concentrated
by evaporation. The product is purified by chromatography on
silica gel RP-18. Water and tetrahydrofuran are used as eluants.
The title compound is obtained as a vitreous solid.
Yield: 2.722 g (54.3% of theory)
Water content: 9.7%
Elementary analysis (relative to anhydrous substance):
Cld: C 33.54 H 3.52 F 32.21 N 8.38 S 3:20
Fnd: C 33.65 H 3.60 F 32.14 N 8.51 S 3.29
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b) Gadolinium complex, monosodium salt of 3,6,9-
tris(carboxymethyl)-3,6,9-triazaundecanedioic acid-mono-N-
~ethyl-2-amino-[carbonylmethyl-amino-(N-ethyl-N-
perfluorooctylsulfonyl)]}-amide
3.259 g (3 mmol, relative to 9.7% water) of the compound
that is produced under 21a) is added to 90 ml of a mixture of
distilled water and ethanol (2:1). While being stirred, 543.8 mg
(1.5 mmol) of gadolinium oxide is added in portions. It is
stirred until dissolved, then the pH of the solution is set at
7.2 by adding sodium hydroxide solution, and it is concentrated
by evaporation, whereby strong foaming occurs. The residue is
codistilled with distilled water. The title compound is obtained
as a glass-like solid.
Yield: 3.861 g (quantitative)
Water content: 8.4%
The elementary analysis is calculated based on anydrous
substance:
Cld: C 28.53 H 2.65 F 27.40 Gd 13.34 N 7.13 Na 1.95 S 2.72
Fnd: C 28.61 H 2.68 F 27.48 Gd 13.40 N 7.08 Na 1.99 S 2.76
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Euample 22
Gadolinium complex, monosodium salt of 3,9-bis(carboxymethyl)-6-
1H,1H,4H,4H,5H,5H,8H,8H,lOH,lOH,11H,11H-2,7-dioxo-3,6-diaza-9-
oxa-perfluoromonodecyl)-3,6,9-triazaundecanedioic acid
a) Glycolic acid-(iH,iH,2H,2H-perfluorodecyl)-ether-N-(2-
aminoethyl)-amide
10.44 g (20 mmol) of compound 2b) is dissolved in 80 ml of
dichloromethane and mixed with 2.30 g (20 mmol) of N-
hydroxysuccinimide as well as 4.13 g (20 mmol) of
dicyclohexylcarbodiimide. It is allowed to stir overnight,
dicyclohexylurea is filtered out, and the filtrate is stirred in
a solution of 60.1 g (1000 mmol) of ethylenediamine in 100 ml of
dichloromethane. It is allowed to stir overnight, mixed with
1.5 1 of water, and the organic phase is separated. The
dichloromethane solution is washed with water, dried on sodium
sulfate, evaporated to the dry state, and the residue is purified
by chromatography on silica gel. A mixture of dichloromethane
with increasing addition of isopropanol is used as eluant.
Yield: 9.615 g (85.2% of theory)
Elementary analysis:
Cld: C 29.80 H 2.32 F 57.24 N 4.96
Fnd: C 29.96 H 2.37 F 57.12 N 5.01
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b) Glycolic acid-(1H,1H,2H,2H-perfluorodecyl)-ether-N-[ethyl-2-
(benzyloxycarbonyl-aminomethylcarbonylamino)]-amide
2.092 g (10 mmol) of benzyloxycarbonylglycine is dissolved
in 15 ml of dichloromethane and mixed with 1.151 g (10 mmol) of
N-hydroxysuccinimide as well as 2.0b3 g (10 mmol) of
dicyclohexylcarbodiimide. It is allowed to stir overnight,
dicyclohexylurea is filtered out and evaporated to the dry state.
The residue is purified on silica gel by column chromatography.
A mixture of dichloromethane and ethanol is used as eluant. The
title compound is obtained as a vitreous solid.
Yield: 6.905 g (91.4% of theory)
Elementary analysis:
Cld: C 38.16 H 2.94 F 42.75 N 5.56
Fnd: C 38.28 H 2.98 F 42.82 N 5.50
c) Glycolic acid-(1H,1H,2H,2H-perfluorodecyl)-ether-N-[ethyl-
(2-aminomethyl-carboxylamino)-amide
3.777 g (5 mmol) of the compound that is produced under 22b)
is hydrogenated in 100 ml of a mixture of tetrahydrofuran and
ethanol at a 2:1 ratio in the presence of 0.2 g of Pearlman's
catalyst (Pd 20%/C) until 112 ml of hydrogen is taken up.
Catalyst is suctioned out, rewashed well with ethanol and
evaporated to the dry state. The title compound is obtained as a
glass-like solid.
Yield: 3.097 g (99.7% of theory)
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Elementary analysis:
Cld: C 30.93 H 2.60 F 51.98 N 6.76
Fnd: C 30.87 H 2.64 F 52.11 N 6.82
d) 3,9-Bis(t-butyloxycarbonylmethyl)-6-
(iH,lH,4H,4H,5H,5H,8H,8H,lOH,lOH,llH,ilH,-2,7-dioxo-3,6-
diaza-9-oxa-perfluorononadecyl)3,6,9-triazaundecanedioic
acid-bis(t-butyleater)
3.107 g (5 mmol) of the amine that is produced under 22c)
and 3.523 g (10 mmol) of N,N-bis(t-butyloxycarbonylmethyl)-2-
(bromoethyl)-amine are added to a mixture of 10 ml of
acetonitrile and 20 ml of phosphate buffer of pH 8 and stirred
intensively for 2 hours at room temperature. Then, the buffer
phase is separated, it is extracted with 10 ml of acetonitrile,
and the latter is added to the organic phase. After 20 ml of
fresh buffer is added, it is stirred for 20 more hours at room
temperature. The organic phase is separated, it is concentrated
by evaporation, and the residue is dispersed between 100 ml of
phosphate buffer (pH 8.0) and 100 ml of ethyl acetate. The
organic phase is washed with saturated common salt solution,
dried on sodium sulfate and concentrated by evaporation. The
compound is purified on silica gel by chromatography.
Dichloromethane with increasing addition of methanol is used as
eluant. The title compound is obtained as a glass-like solid.
Yield: 3.044 g (52.3% of theory)
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Elementary analysis:
Cld: C 45.40 H 5.71 F 27.75 N 6.02
Fnd: C 45.47 H 5.78 F 27.68 N 6.10
e) 3,9-Bis(carboxymethyl)-6-
(lH,iH,4H,4H,5H,5H,8H,8H,lOH,10H,11H,11H-2,7-dioxo-3,6-
diaza-9-oxa-perfluoromonodecyl)-3,6,9-triazaundecanedioic
acid
5.820 g (5 mmol) of the compound that is produced under 22d)
is added to a mixture of 120 ml of trifluoroacetic
acid/dichloromethane at a 2:1 ratio. It is allowed to stir
overnight at room temperature, evaporated to the dry state, the
remainder of trifluoroacetic acid is removed by codistillation
with ethanol and taken up in 240 ml of a mixture of water,
ethanol and chloroform. The solution is set at a constant pH
(about 3) by adding ion exchanger IRA-67 (OH- form). It is
quickly suctioned out, concentrated by evaporation, and the title
compound is obtained as a vitreous solid.
Yield: 3.214 g (68.4% of theory)
Water content: 10.3%
Elementary analysis (relative to anhydrous substance):
Cld: C 35.79 H 3.65 F 34.37 N 7.45
Fnd: C 35.90 H 3.72 F 34.31 N 7.51
a
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f) Gadolinium complex, monosodium salt of 3,9-
bis(carboxymethyl)-6-(iH,lH,4H,4H,5H,5H,8H,8H,lOH,
lOH,llH,ilH-2,7-dioxo-3,6-diaza-9-oxa-perfluorononadecyl)-
3,6,9-triaza-undecanedioic acid
3.143 g (3.0 mmol, relative to 10.3% water content) of the
acid that is produced under 22e) is added to a mixture of 60 ml
of distilled water and 30 ml of ethanol. 543.8 mg (1.5 mmol) of
gadolinium oxide is added in portions while being stirred and
heated to 50°C. After addition is completed, it is stirred until
dissolved. Then, the pH of the solution is set at 7.2 by adding
sodium hydroxide solution, the solution is concentrated by
evaporation, whereby strong foaming can be observed. The residue
is codistilled with distilled water. The title compound is
obtained as a vitreous solid.
Yield: 3.635 g (quantitative)
Water content: 7.9%
Elementary analysis (relative to anhydrous substance):
Cld: C 30.14 H 2.71 F 28.95 Gd 14.09 N 6.28 Na 2.06
Fnd: C 30.21 H 2.78 F 29.03 Gd 14.16 N 6.22 Na 2.11
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Exampls 23
Gadolinium complex of 3,6,9-tris(carboxymethyl)-3,6,9-
triazaundecanedioic acid-bis{N-[2-aminoethyl-(N-ethyl-N-
perfluorooctylsulfonyl]-amide}
a) N-Ethyl-(2-benzyloxycarbonylamino-ethyl)-
perfluorooctylsulfonic acid amide
5.272 g (10 mmol) of perfluorooctylsulfonic acid-N-
ethylamide is dissolved in 30 ml of dimethylformamide. With
exclusion of moisture, it is mixed with 330 mg (11 mmol) of
sodium hydride (80% in oil). After gas generation is completed,
the solution of 2.093 g (10 mmol) of N-benzyloxycarbonyl-
aziridine is added dropwise to it. It is poured into 300 ml of
ice water, extracted with dichloromethane, the organic solution
is washed with water, it is dried on sodium sulfate and
evaporated to the dry state. The residue is chromatographed on
silica gel with dichloromethane/methanol. The title compound is
a glass-like solid.
Yield: 6.149 g (87.3% of theory)
Elementary analysis:
Cld: C 34.10 H 2.43 F 45.85 N 3.98 S 4.55
Fnd: C 34.00 H 2.49 F 45.97 N 4.06 S 4.49
b) N-Ethyl-N-2-(aminoethyl)-perfluorooctylsulfonamide
3.522 g (5 mmol) of the compound that is produced under 23a)
is hydrogenated in 100 ml of a mixture of tetrahydrofuran and
ethanol at a 2:1 ratio in the presence of 0.2 g of Pearlman's
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catalyst (Pd 20%/C) until 112 ml of hydrogen is taken up.
Catalyst is suctioned out, it is rewashed well with ethanol and
evaporated to the dry state. The title compound is obtained as
an amorphous solid.
Yield: 2.814 g (98.7% of theory)
Elementary analysis:
Cld: C 25.27 H 1.94 F 56.64 N 4.91 S 5.62
Fnd: C 25.39 H 1.99 F 56.57 N 4.96 S 5.53
c) 3,6,9-Tris(carboxymethyl)-3,6,9-triazaundecanedioic acid-
bis{N-[2-aminoethyl-(N-ethyl-N-perfluorooctylsulfonyl)]-
amide}
5.703 g (10 mmol) of the compound that is produced under
23b) as well as 1.518 g (15 mmol) of triethylamine are dissolved
in 30 ml of dry dimethylformamide and mixed in portions with
1.787 g (5 mmol) of diethylenetriaminepentaacetic acid-
bisanhydride while being stirred and with exclusion of moisture.
It is allowed to stir overnight, then concentrated by
evaporation, mixed with water, the pH is set at about 3 with 3N
hydrochloric acid, and it is extracted twice with 100 ml of n-
butanol each. The organic solutions are combined, concentrated
by evaporation and subjected to a chromatography on silica gel
RP-18. Water and tetrahydrofuran are used as eluant. The title
compound is obtained as a glass-like solid.
Yield: 6.172 g (82.4% of theory)
Water content: 9.8%
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Elementary analysis (relative to anhydrous substance):
Cld: C 30.47 H 2.76 F 43.12 N 6.55 S 4.28
Fnd: C 30.59 H 2.81 F 43.00 N 6.61 S 4.33
d) Gadolinium complex of 3,6,9-tris(carboxymethyl)-3,6,9-
triazaundecanedioic acid-bis{N-[2-aminoethyl-(N-ethyl-N-
perfluorooctylsulfonyl)]-amide}
6.570 g (4 mmol, relative to 9.8% water content) of the
compound that is produced under 23c) is added to a mixture of 120
ml of distilled water, 60 ml of ethanol and 20 ml of chloroform.
725 mg (82.0 mmol) of gadolinium oxide is added in portions while
being stirred and heated to 50°C. It is stirred until dissolved,
then concentrated by evaporation, whereby strong foaming occurs,
and the residue is subjected to codistillation with distilled
water. The codistillation is repeated twice. The title compound
is obtained as a glass-like solid.
Yield: 7.191 g (quantitative)
Water content: 8.1%
Elementary analysis (relative to anhydrous substance):
Cld: C 27.63 H 2.32 F 39.10 Gd 9.52 N 5.93 S 3.88
Fnd: C 27.50 H 2.37 F 39.22 Gd 9.61 N 5.85 S 3.95
f
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Example 24
Gadolinium complex of 3,6,9-tris(carboxymethyl)-3,6,9-
triazaundecanedioic acid-bis{N-<2-aminoethyl-[glycolic acid-
(iH,lH,2H,2H-perfluorodecyl-ether)-amide]>-amide}
a) 3,6,9-Tris(carboxymethyl)-3,6,9-triazaundecanedioic acid-
bis{N-<2-aminoethyl-glycolic acid-(lH,iH,2H,2H-
perfluorodecyl-ether)-amide]>-amide}
6.771 g (12 mmol) of the compound that is produced under
Example 22a) as well as 1.821 g (18 mmol) of triethylamine are
dissolved in 40 ml of dry dimethylformamide and mixed in portions
with 2.144 g (6 mmol) of diethylenetriaminepentaacetic acid-
bisanhydride while being stirred and with exclusion of moisture.
It is allowed to stir overnight, then concentrated by
evaporation, mixed with 20 ml of water, the pH is set at about 3,
and it is extracted with 3N hydrochloric acid twice with 150 ml
of butanol each. The organic solutions are combined,
concentrated by evaporation, and the residue is subjected to a
chromatography on silica gel RP-18. Water and tetrahydrofuran
are used as eluant. The title compound is obtained as a glass-
like solid.
Yield: 6.989 g (78.4% of theory)
Water content: 7.1%
Elementary analysis (relative to anhydrous substance):
Cld: C 33.95 H 3.05 F 43.47 N 6.60
Fnd: C 34.06 H 3.11 F 43.40 N 6.6?
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b) Gadolinium complex of 3,6,9-tris(carboxymethyl)-3,6,9-
triazaundecanedioic acid-bis{N-<2-aminoethyl-[glycolic acid-
(iH,lH,2H,2H-perfluorodecyl-ether)-amide]>-amide}
4.798 g (3 mmol, relative to 7.1% water) of the compound
that is produced under 24a) is added to a mixture of 100 ml of
distilled water, 50 ml of ethanol and 20 ml of chloroform. 543.8
mg (1.5 mmol) of gadolinium oxide is added in portions while
being stirred and heated to 50°C. It is stirred until dissolved,
then concentrated by evaporation, whereby strong foaming occurs.
The residue is codistilled several times with distilled water.
The title compound is obtained as a glass-like solid.
Yield: 5.285 g (quantitative)
Water content: 6.9%
The elementary analysis is calculated based on anydrous
substance.
Cld: C 30.76 H 2.58 F 39.39 Gd 9.59 N 5.98
Fnd: C 30.87 H 2.65 F 39.51 Gd 9.69 N 6.11
Example 25
Gadolinium complex, sodium salt of 3,9-bis(carboxymethyl)-6-[N-
(lH,iH,2H,2H-perfluorodecyl)-aminocarbonylmethyl-3,6,9-
triazaundecanedioic acid
a) N-Benzyloxycarbonylglycine-N-(1H,1H,2H,2H-perfluorodecyl)-
amide
7.877 g (15 mmol) of 1H,1H,2H,2H-perfluorodecylamine (J.
Fluor. Chem. ~5, 85 (1991)) is dissolved in 70 ml of
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dichloromethane and mixed with 1.726 g (15 mmol) of N-
hydroxysuccinimide, 3.095 g (15 mmol) of dicyclohexylcarbodiimide
and 3.138 g (15 mmol) of N-benzyloxycarbonylglycine (commercially
available products, Bachem). It is allowed to stir overnight,
the dicyclohexylurea is filtered off, concentrated by
evaporation, and the residue is subjected to column
chromatography on silica gel. Mixtures of dichloromethane and
ethanol are used as eluant. The title compound is obtained as a
solid.
Yield: 8.951 g (91.2% of theory)
Elementary analysis:
Cld: C 36.71 H 2.31 F 49.36 N 4.28
Fnd: C 36.87 H 2.39 F 49.51 N 4.37
b) Glycine-N-(1H,1H,2H,2H-perfluorodecyl)-amide
7.594 g (10 mmol) of the compound that is produced under
28a) is dissolved in 150 ml of a mixture of tetrahydrofuran and
ethanol at a 2:1 ratio and hydrogenated in the presence of 0.25 g
of Pearlman's catalyst (Pd 20%/C) until 224 ml of hydrogen is
taken up. Catalyst is suctioned out, rewashed well with ethanol
and evaporated to the dry state. The title compound is obtained
as an amorphous solid.
Yield: 6.21 g (99.3% of theory)
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Elementary analysis:
Cad: C 25.37 H 1.60 F 56.84 N 4.93
Fnd: C 25.28 H 1.65 F 56.92 N 4.99
c) 3,9-Bis(t-butyloxycarbonylmethyl)-6-N-[iH,lH,2H,2H-
perfluorodecyl)-aminocarbonylmethyl-3,6,9-
triazaundecanedioic acid-di(t-butylester)
2.841 g (5 mmol) of the amine that is produced under 25b)
and 3.875 g (11 mmol) of N,N-bis(t-butyloxycarbonylmethyl)-2-
(bromoethyl)-amine are added to a mixture of 10 ml of
acetonitrile and 20 ml of phosphate buffer of pH 8.0, and it is
stirred intensively at room temperature for 2 hours. Then, the
buffer phase is separated, it is extracted with 10 ml of
acetonitrile, and the latter is added to the organic phase.
After 20 ml of fresh buffer is added, it is stirred for 20 more
hours at room temperature. The organic phase is separated,
concentrated by evaporation, and the residue is dispersed between
100 ml of phosphate buffer (pH 8.0) and 100 ml of ethyl acetate.
The organic phase is washed with saturated common salt solution,
dried on sodium sulfate and concentrated by evaporation. The
title compound is purified by chromatography on silica gel.
Dichloromethane with increasing addition of methanol is used as
eluant. The title compound is obtained as a glass-like solid.
Yield: 4.161 g (78.3$ of theory)
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Elementary analysis:
Cld: C 45.20 H 5.59 F 30.39 N 5.27
Fnd: C 45.35 H 5.67 F 30.47 N 5.34
d) 3,9-Bis(carboxymethyl)-6-N-(1H,1H,2H,2H-perfluorodecyl)
aminocarbonylmethyl-3,6,9-triazaundecanedioic acid
4.783 g (4.5 mmol) of the compound that is produced under
25c) is added to a mixture of 100 ml of trifluoroacetic
acid/dichloromethane at a 2:1 ratio. It is allowed to stir
overnight at room temperature, then evaporated to the dry state,
the remainder of trifluoroacetic acid is removed by
codistillation with ethanol and taken up in 160 ml of a mixture
of water, ethanol and chloroform (10:5:1). A pH of about~3 (pH
constant) is set by adding ion exchanger IRA-67 (OH' form). It
is suctioned out quickly, concentrated by evaporation, and the
title compound is obtained as a vitreous solid.
Yield: 3.007 g (79.7% of theory)
Water content: 10.9%
Elementary analysis (relative to anhydrous substance):
Cld: C 34.38 H 3.25 F 38.52 N 6.68
Fnd: C 34.29 H 3.33 F 38.65 N 6.77
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e) Gadolinium complex, monosodium salt of 3,9-
bis(carboxymethyl)-6-N-(lH,iH,2H,2H-perfluorodecyl)-
aminocarbonylmethyl)-3,6,9-triazaundecanedioic acid
2.823 g (3.0 mmol, relative to 10.9% water content) of the
acid that is produced under Example 25d) is added to a mixture of
60 ml of distilled water and 30 ml of ethanol. 543.8 mg (1.5
mmol) of gadolinium oxide is added in portions while being
stirred and heated to 50°C. After addition is completed, it is
stirred until dissolved. Then, the pH of the solution is set at
7.2 by adding sodium hydroxide solution. The solution is
concentrated by evaporation. In this case, strong foaming
occurs. The residue is codistilled twice with distilled water.
The title compound is obtained as a vitreous solid.
Yield: 3.353 g (quant)
Water content: 9.2%
The elementary analysis is calculated based on anydrous
substance.
Cld: C 28.41 H 2.28 F 31.83 Gd 15.50 N 5.52 Na 2.27
Fnd: C 28.51 H 2.33 F 31.76 Gd 15.57 N 5.46 Na 2.35
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Exempla 26
Gadolinium complex, disodium salt of 3,6,9-tris(carboxymethyl)-4-
[N-iH,iH,2H,2H-perfluorodecyloxy)-benzyl]-3,6,9-triaza-
undecanedioic acid
a) 3,6,9-Tris-(t-butyloxycarbonylmethyl)-4-[4-(lH,iH,2H,2H-
perfluorodecyloxy)-benzyl]-3,6,9-triazaundecanedioic acid-
di(t-butylester)
6.131 g (5 mmol) of 3,6,9-tris(t-butyloxycarbonylmethyl)-4-
(4-hydroxybenzyl)-3,6,9-triazaundecanedioic acid-di(t-
butylester), produced according to PCT WO 88/07521, is added to
50 ml of dry dimethylformamide, and it is mixed in portions with
150 g (5 mmol) of sodium hydride (80% in oil) while being stirred
and with exclusion of moisture. After dissolving is completed,
it is mixed with 3.092 g (5 mmol) of the tosylate that is
produced under Example 7a). It is stirred for 12 hours at 40°C.
Then, it is poured into 500 ml of ice water, the product is taken
up in dichloromethane, the organic solution is washed with water,
dried on sodium sulfate and evaporated to the dry state. The
residue is purified by chromatography on silica gel. A mixture
of dichloromethane, isopropanol, hexane at a 20:1:5 ratio is used
as eluant.
The title compound is obtained as an amorphous solid.
Yield: 5.015 g (81.8% of theory)
Elementary analysis:
Cld: C 49.96 H 5.92 F 26.34 N 3.43
Fnd: C 50.11 H 6.00 F 26.43 N 3.38
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b) 3,6,9-Tris(carboxymethyl)-4-[4-(1H,1H,2H,2H-
perfluorodecyloxy)-benzyl]-3,6,9-triazaundecanedioic acid
3.678 g (3 mmol) of the compound that is produced under
Example 26a) is dissolved in 100 ml of a mixture of
trifluoroacetic acid and dichloromethane at a 2:1 ratio, and it
is stirred overnight at room temperature. It is evaporated to
the dry state, and the remainder of trifluoroacetic acid is
removed by codistillation with ethanol. The residue is taken up
in 160 ml of a mixture of water, ethanol and chloroform (10:5:1).
By adding ion exchanger IR A-67 (OH- form), a pH of about 3
(constant pH) is set. It is quickly suctioned out, concentrated
by evaporation, and the title compound is obtained as a vitreous
solid.
Yield: 2.357 g (83.1% of theory)
Water content: 11.3%
The elementary analysis is calculated based on anydrous
substance.
Cld: C 39.38 H 3.41 F 34.16 N 4.44
Fnd: C 39.52 H 3.47 F 34.32 N 4.36
c) Gadolinium complex, disodium salt of 3,6,9-
tris(carboxymethyl)-4-[N-(iH,lH,2H,2H-perfluorodecyloxy)-
benzyl]-3,6,9-triaza-undecanedioic acid
3.145 g (3.0 mmol, relative to 11.3% water content) of the
acid that is produced under Example 26b) is added to a mixture of
60 ml of distilled water and 30 ml of ethanol. 543.8 mg (1.5
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mmol) of gadolinium oxide is added in portions while being
stirred and heated to 50°C. After addition is completed, it is
stirred until dissolved. Then, the pH of the solution is set at
7.2 by adding sodium hydroxide solution, and it is concentrated
by evaporation. In this case, strong foaming occurs. The
residue is codistilled twice with distilled water. The title
compound is obtained as a vitreous solid.
Yield: 3.804 g (quantitative)
Water content: 9.8%
Elementary analysis (relative to anhydrous substance):
Cld: C 32.55 H 2.38 F 28.24 Gd 13.75 N 3.67 Na 4.02
Fnd: C 32.44 H 2.43 F 28.30 Gd 13.66 N 3.71 Na 4.10
Example 27
Gadolinium complex of 10-[(-perfluorooctyl-sulfonyl)-piperazin-1-
yl-carbonylmethyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane
a) 1-Perfluorooctylsulfonyl-piperazine
34.39 g (398.3 mmol) of piperazine, 50 g (99.6 mmol) of
perfluorooctylsulfonyl fluoride and 10.12 g (100 mmol) of
triethylamine are heated for 24 hours to 85°C. 500 ml of water
is added, and it is extracted twice with 200 ml of
dichloromethane each. The organic phase is dried on magnesium
sulfate and evaporated to the dry state in a vacuum. The residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/2-propanol = 25:1).
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Yield: 17.55 g (31% of theory) of a colorless, amorphous
solid
Elementary analysis:
Cld: C 25.36 H 1.60 F 56.84 N 4.93 S 5.64
Fnd: C 25.15 H 1.80 F 56.65 N 4.81 S 5.70
b) 1-(2-Bromoacetyl)-4-perfluorooctylsulfonyl-piperazine
17 g (29.9 mmol) of the title compound of Example 27a) and
5.1 g (50 mmol) of triethylamine are dissolved in 100 ml of
dichloromethane. 9.1 g (44.9 mmol) of bromoacetyl bromide is
added in drops at -10°C within 30 minutes, and it is stirred for
2 hours at 0°C. The solution is poured into 200 ml of 2N
hydrochloric acid and stirred thoroughly. The organic phase is
separated, dried on magnesium sulfate and concentrated by
evaporation in a vacuum. The residue is chromatographed on
silica gel (mobile solvent: dichloromethane/acetone = 20/1).
Yield: 18.55 g (90% of theory) of a slightly yellow-
colored waxy solid
Elementary analysis:
Cld: C 24.40 H 1.46 F 46.86 N 4.06 S 4.65 Br 11.59
Fnd: C 24.22 H 1.60 F 46.75 N 3.97 S 4.48 Br 11.41
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c) 10-[(-Perfluorooctyl-sulfonyl)-piperazin-1-yl-
carbonylmethyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane
4.63 g (13.36 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane (~ D03A) and 18.5 g (133.6 mmol) of
potassium carbonate are added to 17.78 g (20 mmol) of the title
compound of Example 27b) in 180 ml of methanol. It is refluxed
for 12 hours. The inorganic salts are filtered off, and the
filtrate is evaporated to the dry state. The residue is taken up
in 100 ml of water and set at pH 3 with 5N hydrochloric acid. It
is extracted twice with 150 ml of n-butanol. The combined
organic phases are evaporated to the dry state in a vacuum, and
the residue is purified by RP-chromatography (RP-18/mobile
solvent = gradient consisting of water/n-butanol/acetonitrile).
Yield: 12.79 g (67% of theory) of a colorless solid
Water content: 8.5%
Elementary analysis (relative to anhydrous substance):
Cld: C 35.23 H 3.70 F 33.83 N 8.80 S 3.36
Fnd: C 35.17 H 3.81 F 33.67 N 8.65 S 3.18
d) Gadolinium complex of 10-[(-perfluorooctyl-sulfonyl)-
piperazin-1-yl-carbonylmethyl]-1,4,7-tris(carboxymethyl)-
1,4,7,10-tetraazacyclododecane
g (10.47 mmol) of the title compound of Example 27c) is
dissolved in a mixture of 50 ml of water/20 ml of ethanol, and
1.90 g (5.23 mmol) of gadolinium oxide is added. It is stirred
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for 4 hours at 80°C. The solution is filtered and evaporated to
the dry state in a vacuum.
Yield: 12.2 g (quantitative)
Water content: 5.1%
Elementary analysis (relative to anhydrous substance):
Cld: C 30.33 H 2.91 F 29.13 Gd 14.18 S 2.89
Fnd: C 30.39 H 2.81 F 29.02 Gd 14.01 S 2.78
Example 28
Gadolinium complex, monosodium salt of 3,9-bis(carboxymethyl)-6-
[(4-perfluorooctylsulfonyl)-piperazine-1-carbonylmethyl]-3,6,9-
triazaundecanedioic acid
a) 1-(2-Benzyloxycarbonylamino)-methyl-carbonyl-4-
(perfluorooctylsulfonyl)-piperazine
8.524 g (15 mmol) of the piperazine derivative that is
produced under 27a) is dissolved in 80 ml of dichloromethane and
mixed with 1.726 g (15 mmol) of N-hydroxysuccinimide, 3.095 g (15
mmol) of dicyclohexylcarbodiimide and 3.138 g (15 mmol) of N-
benzyloxycarbonylglycine (commercially available products,
Bachem). It is allowed to stir overnight, the dicyclohexylurea
is filtered off, concentrated by evaporation, and the residue is
subjected to column chromatography on silica gel. Mixtures of
dichloromethane and ethanol are used as eluant. The title
compound is obtained ae a solid.
Yield: 10.16 g (89.2% of theory)
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Elementary analysis:
Cld: C 34.79 H 2.39 F 42.53 N 5.53 S 4.22
Fnd: C 34.60 H 2.43 F 42.65 N 5.66 S 4.17
b) 1-(2-Amino)-acetyl-4-(perfluorooctyl)-sulfonyl-piperazine
7.594 g (10 mmol) of the compound that is produced under
28a) is dissolved in 150 ml of a mixture of tetrahydrofuran and
ethanol at a 2:1 ratio, and it is hydrogenated in the presence of
0.25 g of Pearlman's catalyst (Pd 20%/C) until 224 ml of hydrogen
is taken up. Catalyst is suctioned out, rewashed well with
ethanol and evaporated to the dry state. The title compound is
obtained as an amorphous solid.
Yield: 6.21 g (99.3% of theory)
Elementary analysis:
Cld: C 26.89 H 1.93 F 51.65 N 6.72 S 5.13
Fnd: C 27.03 H 1.97 F 51.77 N 6.58 S 5.20
c) 3,9-Bis(t-butyloxycarbonylmethyl)-6-[(4-
perfluorooctylsulfonyl)-piperazine-1-carbonylmethyl]-3,6,9-
triazaundecanedicarboxylic acid-di(t-butylester)
3.127 g (5 mmol) of the amine that is produced under 28b)
and 3.875 g (1l mmol) of N,N-bis(t-butyloxycarbonylmethyl)-2-
(bromoethyl)-amine are added to a mixture of 10 ml of
acetonitrile and 20 ml of phosphate buffer of pH 8.0, and it is
stirred intensively at room temperature for 2 hours. Then, the
buffer is separated, extracted with 10 ml of acetonitrile, and
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the latter is added to the organic phase. After 20 ml of fresh
buffer is added, it is stirred for 20 more hours at room
temperature. The organic phase is separated, concentrated by
evaporation, and the rssidue is dispersed between 100 ml of
phosphate buffer (pH 8.0) and 100 ml of ethyl acetate. The
organic phase is washed with saturated common salt solution,
dried on sodium sulfate and concentrated by evaporation. The
title compound is purified by chromatography on silica gel.
Dichloromethane with increasing addition of methanol is used as
eluant. The title compound is obtained as a glass-like solid.
Yield: 4.481 g (76.3% of theory)
Elementary analysis:
Cld: C 43.71 H 5.42 F 27.99 N 4.85 S 2.78
Fnd: C 43.84 H 5.47 F 28.10 N 5.00 S 2.69
d) 3,9-Bis(carboxymethyl)-6-[(4-perfluorooctyl-sulfonyl)-
piperazin-1-yl-carbonylmethyl]-3,6,9-triazaundecanedioic
acid
5.193 g (4.5 mmol) of the compound that is produced under
28c) is added to a mixture of 100 ml of trifluoroacetic
acid/dichloromethane at a 2:1 ratio. It is allowed to stir
overnight at room temperature, then evaporated to the dry state,
the remainder of the trifluoroacetic acid is removed by
codistillation with ethanol and taken up in 160 ml of a mixture
of water, ethanol and chloroform (10:5:1). A pH of about 3
(constant pH) is set by adding ion exchanger IRA-67 (OH' form).
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It is quickly suctioned out, concentrated by evaporation, and the
title compound is obtained as a vitreous solid.
Yield: 3.718 g (79.2% of theory)
Water content: 10.9%
Elementary analysis (relative to anhydrous substance):
Cld: C 33.59 H 3.25 F 34.74 N 6.03 S 3.45
Fnd: C 33.69 H 3.36 F 34.82 N 6.10 S 3.38
e) Gadolinium complex, monosodium salt of 3,9-
bis(carboxymethyl)-6-[(4-perfluorooctylsulfonyl)-piperazine-
1-carbonylmethyl]-3,6,9-triazaundecanedioic acid
3.13 g (3.0 mmol, relative to 10.9% water content) of the
acid that is produced under Example 28d) is added to a mixture of
60 ml of distilled water and 30 ml of ethanol. 543.8 mg (1.5
mmol) of gadolinium oxide is added in portions while being
stirred and heated to 50°C. After addition is completed, it is
stirred until dissolved. Then, the pH of the solution is set at
7.2 by adding sodium hydroxide solution, and it is concentrated
by evaporation. In this case, strong foaming occurs. The
residue is codistilled twice with distilled water. The title
compound is obtained as a vitreous solid.
Yield: 3.678 g (quantitative)
Water content: 9.2%
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Elementary analysis (relative to anhydrous substance):
Cld: C 28.24 H 2.37 F 29.21 Gd 14.22 N 5.07 Na 2.08 S 2.90
Fnd: C 28.36 H 2.41 F 29.14 Gd 14.30 N 5.15 Na 2.12 S 2.83
Esampl~ 29
Gadolinium complex of 3,6,9-tris(carboxymethyl)-3,6,9-
triazaundecanedioic acid-bis((4-perfluorooctylsulfonyl)-
piperazine]-amide
a) 3,6,9-Tris(carboxymethyl)-3,6,9-triazaundecanedioic acid-
bis[(4-perfluorooctylsulfonyl)-piperazine]-amide
5.683 g (10 mmol) of the compound produced under 27a) as
well as 1.518 g (15 mmol) of triethylamine are dissolved in 30 ml
of dry dimethylformamide and mixed in portions with 1.787 g (5
mmol) of diethylenetriaminepentaacetic acid-bisanhydride while
being stirred and with exclusion of moisture. It is allowed to
stir overnight, then concentrated by evaporation, mixed with
water, the pH is set at about 3 with 3N hydrochloric acid, and it
is extracted twice with 100 ml of n-butanol each. The organic
solutions are combined, concentrated by evaporation and subjected
to a chromatography on silica gel RP-18. Water and
tetrahydrofuran are used as eluant. The title compound is
obtained as a glass-like solid.
Yield: 6.741 g (81.4% of theory)
Water content: 9.8%
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Elementary analysis (relative to anhydrous substance):
Cld: C 30.55 H 2.50 F 43.24 N 6.56 S 4.29
Fnd: C 30.67 H 2.55 F 43.33 N 6.49 S 4.21
b) Gadolinium complex of 3,6,9-tris(carboxymethyl)-3,6,9-
triazaundecanedioic acid-bis[(4-perfluorooctylsulfonyl)-
piperazine]-amide
6.570 g (4 mmol, relative to 9.8% water content) of the
compound that is produced under 23c) is added to a mixture of 120
ml of distilled water, 60 ml of ethanol and 20 ml of chloroform.
While being stirred and heated to 50°C, 725 mg (82.0 mmol) of
gadolinium oxide is added in portions. It is stirred until
dissolved, then concentrated by evaporation, whereby strong
foaming occurs, and the residue is subjected to codistillation
with distilled water. Codistillation is repeated twice. The
title compound is obtained as a glass-like solid.
Yield: 7.191 g (quantitative)
water content: 8.1%
Elementary analysis (relative to anhydrous substance):
Cld: C 27.69 H 2.08 F 39.19 Gd 9.54 N 5.95 S 3.89
Fnd: C 27.83 H 2.15 F 39.10 Gd 6.91 N 6.03 S 3.88
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Fxample 30
a) 11-[N-Ethyl-N-(perfluorooctylsulfonyl)-amino]undecanoic acid
benzyl ester
20 g (37.94 mmol) of N-ethyl-N-perfluorooctylsulfonamide and
15.73 g (113.8 mmol) of potassium carbonate are suspended in 200
ml of acetone, and 26.96 g (75.87 mmol) of 11-bromoundecanoic
acid benzyl ester is added in drops at 60°C. It is stirred for 3
hours at 60°C. Salts are filtered out, and the filtrate is
evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
hexane/dichloromethane/acetone = 10/10/1). After the product-
containing fractions are concentrated by evaporation, the residue
is recrystallized from methanol/ether.
Yield: 26.46 g (87% of theory) of a colorless, crystalline
powder.
Elementary analysis:
Cld: C 41.95 H 4.02 N 1.75 F 40.29 S 4.00
Fnd: C 41.78 H 4.17 N 1.68 F 40.12 S 3.88
b) 11-jN-Ethyl-N-(perfluorooct~lsulfonvl)-aminoundecanoic acid
20 g (24.95 mmol) of the title compound of Example 30a) is
dissolved in 300 ml of isopropanol/200 ml of dichloromethane, and
3 g of palladium catalyst (10% Pd/C) is added. It is
hydrogenated overnight at room temperature. Catalyst is filtered
out, and the filtrate is evaporated to the dry state in a vacuum.
The residue is recrystallized from ether/hexane.
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Yield: 16.69 g (94% of theory) of a colorless, crystalline
solid.
Elementary analysis:
Cld: C 35.45 H 3.68 N 1.97 F 45.39 S 4.51
Fnd: C 35.31 H 3.81 N 1.85 F 45.25 S 4.42
c) Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-16-aza-16-
(perfluorooctylsulfonyl-octadecyl]-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
12.16 g (17.09 mmol) of the title compound of Example 30b)
and 1.97 g (18.79 mmol) of N-hydroxysuccinimide are dissolved in
a mixture of 50 ml of dimethylformamide/50 ml of chloroform. At
0°C, 3.88 g (18.79 mmol) of dicyclohexylcarbodiimide is added and
stirred for 1 hour at 0°C, then for 3 hours at room temperature.
It is cooled again to 0°C, and 5.19 g (51.27 mmol) of
triethylamine/50 ml of 2-propanol is added. Then, 10.78 g (18.79
mmol) of the gadolinium complex of 10-(3-amino-2-hydroxypropyl)-
1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (WO
95/17451), dissolved in 50 ml of water, is added, and it is
stirred for 3 hours at room temperature. It is evaporated to the
dry state, the residue is taken up in a mixture of 200 ml of
methanol/100 ml of chloroform, and dicyclohexylurea is filtered
out. The filtrate is evaporated to the dry state and purified by
RP-chromatography (RP-18/mobile solvent: gradient consisting of
water/N-propanol/acetonitrile).
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Yield: 16.82 g (71% of theory) of a colorless, vitreous
solid.
Water content: 8.6%
Elementary analysis (relative to anhydrous substance):
Cld: C 36.02 H 4.30 F 25.49 Gd 12.41 N 6.63 S 2.53
Fnd: C 35.87 H 4.45 F 25.28 Gd 12.29 N 6.50 S 2.41
d) 10-[2-Hydroxy-4-aza-5-oxo-16-aza-16-(perfluorooctylsulfonyl-
octadecyl]-1,4,7-tris(carboxymethylj-1,4,7,10-
tetraazacyclododecane
11.1 g (8.76 mmolj of the title compound of Example 30c) is
dissolved in a mixture of 100 ml of water/100 ml of ethanol, and
1.73 g (13.71 mmol) of oxalic acid-dihydrate is added. It is
heated for 8 hours to 80°C. It is cooled to 0°C, and
precipitated gadolinium oxalate is filtered out. The filtrate is
evaporated to the dry state, and the residue is purified on RP-18
(RP-18/ mobile solvent: gradient consisting of water/i-
propanol/acetonitrile).
Yield: 9.80 g (92% of theory) of a vitreous solid.
Water content: 8.5%
Elementary analysis (relative to anhydrous substance):
Cld: C 41.01 H 5.16 F 29.02 N 7.55 S 2.88
Fnd: C 40.87 H 5.31 F 28.85 N 7.40 S 2.73
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e) Ytterbium complex of 10-[2-hydroxy-4-aza-5-oxo-16-aza-16-
(perfluoroctylsulfonyl-octadecyl]-1,4,7-tris(carboxymethyl)-
1,4,7,10-tetraazacyclododecane
1.33 g (2.53 mmol) of ytterbium carbonate is added to 5.64 g
(5.07 mmol) of the title compound of Example 30d) in 100 ml of
water/50 ml of ethanol, and it is stirred for 3 hours at 80°C.
The solution is filtered, and the filtrate is evaporated to
the dry state in a vacuum.
Yield: 7.08 g (quantitative) of a vitreous solid.
Water content: 8.1%
Elementary analysis (relative to anhydrous substance):
Cld: C 35.58 H 4.24 F 25.17 N 6.55 S 2.50 Yb 13.49
Fnd: C 35.43 H 4.37 F 25.05 N 6.48 S 2.39 Yb 13.35
f) Dysprosium complex of 10-[2-hydroxy-4-aza-5-oxo-16-aza-16-
(perfluoroctylsulfonyl-octadecyl]-1,4,7-tris(carboxymethyl)-
1,4,7,10-tetraazacyclododecane
0.95 g (2.53 mmol) of dysprosium oxide is added to 5.64 g
(5.07 mmol) of the title compound of Example 30d) in 100 ml of
water/50 ml of ethanol, and it is stirred for 3 hours at 80°C.
The solution is filtered, and the filtrate is evaporated to the
dry state in a vacuum.
Yield: 7.10 g (quantitative) of a colorless, vitreous
solid.
Water content: 9.1%
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Elementary analysis (relative to anhydrous substance):
Cld: C 35.87 H 4.28 F 25.38 N 6.60 S 2.52 Dy 12.77
Fnd: C 35.69 H 4.39 F 25.18 N 6.49 S 2.43 Dy 12.70
Example 31
a) 11,11,11,10,10,9,9,8,8,7,7-Tridecafluoro-3-oxaundecanoic
acid-tert-butyl ester
19.51 g (100.0 mmol) of bromoacetic acid-tert-butyl ester is
added in drops to a mixture of 27.57 g (75.73 mmol) of
iH,iH,2H,2H-perfluorooctan-1-of and 2.57 g (7.57 mmol) of
tetrabutylammonium hydrogen sulfate in 300 ml of 60% aqueous
potassium hydroxide solution/200 ml of toluene while being
stirred vigorously at 0°C. It is stirred for one hour at 0°C,
the organic phase is separated, and the aqueous phase is
extracted twice with 50 ml of toluene. The combined organic
extracts are dried on sodium sulfate and concentrated by
evaporation in a vacuum. The residue is chromatographed on
silica gel (mobile solvent: dichloromethane).
Yield: 28.97 g (80% of theory) of a colorless oil.
Elementary analysis:
Cld: C 35.16 H 3.16 F 51.64
Fnd: C 35.08 H 3.20 F 51.70
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b) 11,11,11,10,10,9,9,8,8,7,7-Tridecafluoro-3-oxaundecanoic
acid
25.29 g (52.88 mmol) of the title compound of Example la) is
dissolved in 300 ml of trifluoroacetic acid, and it is stirred
overnight at room temperature. It is evaporated to the dry state
in a vacuum, and the residue is recrystallized from
hexane/diethyl ether.
Yield: 20.54 g (92% of theory) of a colorless, crystalline
solid.
Elementary analysis:
Cld: C 28.45 H 1.67 F 58.51
Fnd: C 28.36 H 1.60 F 58.62
c) Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-oxa-
10,10,11,11,12,12,13,13,14,14,15,15,15-tridecafluoro-
pentadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane
7.21 g (17.09 mmol) of the title compound of Example 31b and
1.97 g (18.79 mmol) of N-hydroxysuccinimide are dissolved in a
mixture of 50 ml of dimethylformamide/50 ml of chloroform. 3.88
g (18.79 mmol) of dicyclohexylcarbodiimide is added at 0°C, and
it is stirred for 1 hour at 0°C, then for 3 hours at room
temperature. It is cooled again to 0°C, and 5.19 g (51.27 mmol)
of triethylamine/50 ml of 2-propanol is added. Then, 10.78 g
(18.79 mmol) of the gadolinium complex of 10-(3-amino-2-
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hydroxypropyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane (WO 95/17451), dissolved in 50 ml of water,
is added, and it is stirred for 3 hours at room temperature. It
is evaporated to the dry state, the residue is taken up in a
mixture of 200 ml of methanol/100 ml of chloroform, and
dicyclohexylurea is filtered out. The filtrate is evaporated to
the dry state and purified by RP-chromatography (RP-18/mobile
solvent: gradient consisting of water/n-propanol/acetonitrile).
Yield: 12.68 g (71% of theory) of a colorless, vitreous
solid.
Water content: 6.4%
Elementary analysis (relative to anhydrous substance):
Cld: C 33.16 H 3.61 F 25.26 Gd 16.08 N 7.16
Fnd: C 32.85 H 3.84 F 25.01 Gd 15.87 N 7.03
Example 32
a) 15,15,15,14,14,13,13,12,12,11,11,10,10,9,9,8,8-7,7-
Henicosafluoro-3-oxapenta-decanoic acid-tert-butyl ester
19.51 g (100.0 mmol) of bromoacetic acid-tert-butyl ester is
added in drops to a mixture of 42.72 g (75.73 mmol) of
lH,iH,2H,2H-perfluorooctan-1-of and 2.57 g (7.57 mmol) of
tetrabutylammonium hydrogen sulfate in 300 ml of 60% aqueous
potassium hydroxide solution/200 ml of toluene while being
stirred vigorously at 0°C. It is stirred for one hour at 0°C,
the organic phase is separated, and the aqueous phase is
extracted twice with 50 ml of toluene. The combined organic
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extracts are dried on sodium sulfate and concentrated by
evaporation in a vacuum. The residue is chromatographed on
silica gel (mobile solvent: dichloromethane).
Yield: 42.12 g (82% of theory) of a colorless oil.
Elementary analysis:
Cld: C 31.87 H 2.23 F 58.82
Fnd: C 31.73 H 2.20 F 58.90
b) 15,15,15,14,14,13,13,12,12,11,11,10,10,9,9,8,8,7,7-
Henicosafluoro-3-oxapentadecanoic acid-tert-butyl ester
35.87 g (52.88 mmol) of the title compound of Example la) is
dissolved in 300 ml of trifluoroacetic acid, and it is stirred
overnight at room temperature. It is evaporated to the dry state
in a vacuum, and the residue is recrystallized from
hexane/diethyl ether.
Yield: 30.60 g (93% of theory) of a colorless, crystalline
solid.
Elementary analysis:
Cld: C 27.03 H 1.13 F 64.12
Fnd: C 26.91 H 1.20 F 64.02
,,
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c) Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-oxa-
10,10,11,11,12,12,13,13,14,14,15,15,16,16,17,17,18,18,19,19,
19-henicosafluoro-nonadecyl]-1,4,7-tris(carboxymethyl)-
1,4,7-tris(carboxymethylj-1,4,7,10-tetraazacyclododecane
10.63 g (17.09 mmol) of the title compound of Example 32b
and 1.97 g (18.79 mmol) of N-hydroxysuccinimide are dissolved in
a mixture of 50 ml of dimethylformamide/50 ml of chloroform.
3.88 g (18.79 mmolj of dicyclohexylcarbodiimide is added at 0°C,
and it is stirred for 1 hour at 0°C, then for 3 hours at room
temperature. It is cooled again to 0°C, and 5.19 g (51.27 mmolj
of triethylamine/50 ml of 2-propanol is added. Then, 10.78 g
(18.79 mmol) of the gadolinium complex of 10-(3-amino-2-hydroxy-
propyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
(WO 95/17451), dissolved in 50 ml of water, is added, and it is
stirred for 3 hours at room temperature. It is evaporated to the
dry state, the residue is taken up in a mixture of 200 ml of
methanol/100 ml of chloroform, and dicyclohexylurea is filtered
out. The filtrate is evaporated to the dry state and purified by
RP-chromatography (RP-18/mobile solvent: gradient consisting of
water/n-propanol/acetonitrilej.
Yield: 14.73 g (69% of theory) of a colorless, vitreous
solid.
Water content: 5.7%
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Elementary analysis (relative to anhydrous substance):
Cld: C 31.61 H 2.99 F 33.87 Gd 13.35 N 5.95
Fnd: C 31.49 H 3.15 F 33.68 Gd 13.21 N 6.01
Esampla 33
a) N-(2-Bromopropionyl)glycine-benzyl ester
55.9 g (326.1 mmol) of 2-bromopropionic acid chloride is
added in drops to 100 g (296.4 mmol) of glycine benzyl ester-p-
toluenesulfonic acid salt and 33.0 g (326.1 mmol) of
triethylamine in 400 ml of methylene chloride at 0°C. The
temperature is not allowed to exceed 5°C. After the addition is
completed, it is stirred for one hour at 0°C, then for 2 hours at
room temperature. 500 ml of ice water is added, and the water
phase is set at pH 2 with 10% aqueous hydrochloric acid. The
organic phase is separated and washed once each with 300 ml of 5%
aqueous soda solution and 400 ml of water. The organic phase is
dried on magnesium sulfate and evaporated to the dry state in a
vacuum. The residue is recrystallized from diisopropyl ether.
Yield: 68.51 g (75% of theory) of a colorless, crystalline
powder
Melting point: 69-70°C
Elementary analysis:
Cld: C 48.02 H 4.70 N 4.67 Br 26.62
Fnd: C 47.91 H 4.82 N 4.51 Br 26.47
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b) 1-[4-(Benzyloxycarbonyl)-1-methyl-2-oxo-3-azabutyl]-
1,4,7,10-tetraazacyclododecane
50 g (162.2 mmol) of the title compound of Example la) is
added to 55.8 g (324.4 mmol) of 1,4,7,10-tetraazacyclododecane,
dissolved in 600 ml of chloroform, and it is stirred overnight at
room temperature. 500 ml of water is added, the organic phase is
separated, and it is washed twice with 400 ml of water in each
case. The organic phase is dried on magnesium sulfate and
evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
chloroform/methanol/aqueous 25% ammonia = 10/5/1).
Yield: 40.0 g [63% of theory relative to la) used] of a
light yellowish viscous oil.
Elementary analysis:
Cld: C 61.36 H 8.50 N 17.89
Fnd: C 61.54 H 8.68 N 17.68
c) 10-[4-(Benzyloxycarbonyl)-1-methyl-2-oxo-3-azabutyl]-1,4,7-
tris(tert-butoxycarbonylmethyl)-1,4,7,10-
tetraazacyclododecane (sodium bromide complex)
33 g (169 mmol) of bromoacetic acid-tert-butyl ester is
added to 20 g (51.08 mmol) of the title compound of Example 1b)
and 17.91 (169 mmol) of sodium carbonate in 300 ml of
acetonitrile, and it is stirred for 24 hours at 60°C. It is
cooled to 0°C, salts are filtered out, and the filtrate is
evaporated to the dry state. The residue is chromatographed on
a
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silica gel (mobile solvent: ethyl acetate/ethanol: 15/1). The
fractions that contain the product are concentrated by
evaporation, and the residue is recrystallized from diisopropyl
ether.
Yield: 34.62 g (81% of theory) of a colorless, crystalline
powder
Melting point: 116-117°C
Elementary analysis:
Cld: C 54.54 H 7.59 N 8.37 Na 2.74 Br 9.56
Fnd: C 54.70 H 7.65 N 8.24 Na 2.60 Br 9.37
d) 10-(4-Carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7-tris(tert-
butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (sodium
bromide complex)
30 g (35.85 mmol) of the title compound of Example lc is
dissolved in 500 ml of isopropanol, and 3 g of palladium catalyst
(10% Pd/C) is added. It is hydrogenated overnight at room
temperature. Catalyst is filtered out, the filtrate is
evaporated to the dry state in a vacuum and recrystallized from
acetone.
Yield: 22.75 g (85% of theory) of a colorless, crystalline
powder
Melting point: 225°C (decomposition)
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Elementary analysis:
Cld: C 49.86 H 7.69 N 9.38 Na 3.07 Br 10.71
Fnd: C 49.75 H 7.81 N 9.25 Na 2.94 Br 10.58
e) 10-[1-Methyl-2-oxo-3-aza-5-oxo-5-{4-perfluorooctylsulfonyl-
piperazin-1-yl}-pentyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane
g (13.39 mmol) of the title compound of Example 33d and
7.61 g (13.39 mmol) of the title compound of Example 27a are
dissolved in 150 ml of tetrahydrofuran. 3.97 g (16.07 mmol) of
N'-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) is added at
0°C, stirred for 3 hours at 0°C, then for 12 hours at room
temperature. It is evaporated to the dry state in a vacuum. The
residue is taken up in 150 ml of trifluoroacetic acid and stirred
for 12 hours at room temperature. It is evaporated to the dry
state, the residue is dissolved in water and s778et at pH 3.2
with 10% aqueous sodium hydroxide solution. For purification, it
is chromatographed on RP-18 (gradient consisting of
water/acetonitrile/tetrahydrofuran).
Yield: 9.67 g (63% of theory) of a hygroscopic solid.
Water content: 10.5%
Elementary analysis (relative to anhydrous substance):
Cld: C 36.30 H 3.93 N 9.56 F 31.49 S 3.13
Fnd: C 36.14 H 3.98 N 9.40 F 31.67 S 3.02
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f) Gadolinium complex of 10-[1-methyl-2-oxo-3-aza-5-oxo-5-{4-
perfluorooctylsulfonyl-piperazin-1-yl}-pentyl]-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
g (4.87 mmol) of the title compound of Example 33e is
dissolved in 60 ml of water, and 0.883 g (2.44 mmol) of
gadolinium oxide is added. It is stirred for 3 hours at 90°C.
The solution is filtered, and the filtrate is freeze-dried.
Yield: 6.47 g (quantitative) of a voluminous, amorphous
powder
Water content: 11.3%
Elementary analysis (relative to anhydrous substance):
Cld: C 31.56 H 3.16 N 8.31 F 27.37 S 2.72 Gd 13.33
Fnd: C 31.37 H 3.35 N 8.18 F 27.19 S 2.92 Gd 13.05
Example 34
a) 4-Perfluorooctanesulfonylpiperazin-1-ylpentanediamic acid
A solution of 10.b2 g (105.0 mmol) of triethylamine and
59.67 g (105.0 mmol) of the title compound of Example 27a) in 50
ml of tetrahydrofuran sire added in drops to a suspension of 11.41
g (100.0 mmol) of glutaric anhydride in 100 ml of tetrahydrofuran
while being stirred vigorously at 0°C, and it is allowed to come
to room temperature overnight. The reaction mixture is acidified
with 100 ml of 2N HC1 and extracted three times with 100 ml of
tetrahydrofuran. The combined organic extracts are dried with
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sodium sulfate, filtered and concentrated by evaporation. The
residue is recrystallized from 2-propanol/ethyl acetate.
Yield: 52.30 g (73% of theory) of a colorless, crystalline
solid.
Elementary analysis:
Cld: C 29.92 H 2.22 N 4.11 F 47.33 S 4.70
Fnd: C 29.90 H 2.18 N 4.07 F 47.42 S 4.79
b) Gadolinium complex of 10-[2-hydroxy-4-aza-5,9-dioxo-9-{4-
perfluorooctyl)-piperazin-1-yl}-nonyl]-1,4,7-
tris(carboxymethyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane
11.66 g (17.09 mmol) of the title compound of Example 34a
and 1.97 g (18.79 mmol) of N-hydroxysuccinimide are dissolved in
a mixture of 50 ml of dimethylformamide/50 ml of chloroform.
3.88 g (18.79 mmol) of dicyclohexylcarbodiimide is added at 0°C,
and it is stirred for 1 hour at 0°C, then for 3 hours at room
temperature. It is cooled again to 0°C, and 5.19 g (51.27 mmol)
of triethylamine/50 ml of 2-propanol is added. Then, 10.78 g
(18.79 mmol) of the gadolinium complex of 10-(3-amino-2-
hydroxypropyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane (WO 95/17451), dissolved in 50 ml of water,
is added, and it is stirred for 3 hours at room temperature. It
is evaporated to the dry state, the residue is taken up in a
mixture of 200 ml of methanol/100 ml of chloroform, and
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dicyclohexylurea is filtered out. The filtrate is evaporated to
the dry state and purified by RP-chromatography (RP-18/mobile
solvent: gradient consisting of water/n-propanol/acetonitrile).
Yield: 16.7 g (73% of theory) of a colorless, vitreous
solid.
Water content: 7.5%
Elementary analysis (relative to anhydrous substance):
Cld: C 32.99 H 3.50 F 26.09 Gd 12.70 N 7.92 S 2.59
Fnd: C 32.75 H 3.68 F 25.88 Gd 12.55 N 7.84 S 2.63
$xample 35
a) N-Benzylperfluorooctanesulfonamide
50.21 g (100.0 mmol) of perfluorooctanesulfonyl fluoride is
added in drops to a mixture of 10.62 g (105.0 mmol) of
triethylamine and 10.72 g (100.0 mmol) of benzylamine at 80°C
while being stirred vigorously. It is stirred for 2 days at
80°C, the reaction mixture is mixed with 300 ml of water and
extracted 3 times with ethyl acetate. The combined organic
extracts are dried on sodium sulfate, filtered and concentrated
by evaporation. The residue is chromatographed on silica gel
(mobile solvent: dichloromethane/methanol = 4/1).
Yield: 45.96 g (78% of theory) of a colorless liquid
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Elementary analysis:
Cld: C 30.57, H 1.37, N 2.38, S 5.44, F 54.81
Fnd: C 30.49 H 1.30, N 2.42, S 5.50, F 54.90
b) N-Benzyl-N-(perfluorooctylsulfonyl)-aminoacetic acid-t-butyl
ester
22.4 g (37.94 mmol) of the title compound of Example 35a and
15.73 g (113.8 mmol) of potassium carbonate are suspended in 200
ml of acetone, and 14.80 g (75.87 mmol) of bromoacetic acid-tert-
butyl ester is added in drops at 60°C. it is stirred for 3 hours
at 60°C. Salts are filtered out, and the filtrate is evaporated
to the dry state in a vacuum. The residue is chromatographed on
silica gel (mobile solvent: hexane/dichloromethane/acetone =
10/10/1). After the product-containing fractions are
concentrated by evaporation, the residue is recrystallized from
methanol/ether.
Yield: 24.02 g (90% of theory) of a waxy, colorless solid
Elementary analysis:
Cld: C 35.86, H 2.58, N 1.99, S 4.56, F 45.91
Fnd: C 35.67 H 2.71, N 2.13, S 4.45, F 45.83
c) N-Benzyl-N-(perfluorooctylsulfonyl)-aminoacetic acid
20 g (28.43 mmol) of the title compound of Example 35b is
dissolved in 200 ml of trifluoroacetic acid, and it is stirred
overnight at room temperature. It is evaporated to the dry state
in a vacuum. The residue is recrystallized from methanol/ether.
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Yield: 17.48 g (95% of theory) of a colorless, crystalline
solid
Elementary analysis:
Cld: C 31.54, H 1.56, N 2.16, S 4.95, F 49.89
Fnd: C 31.38 H 1.70, N 2.05, S 4.87, F 49.71
d) Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-aza-7-
(perfluorooctylsulfonyl)-8-phenyl-octyl]-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
11.06 g (17.09 mmol) of the title compound of Example 35c
and 1.97 g (18.79 mmol) of N-hydroxysuccinimide are dissolved in
a mixture of 50 ml of dimethylformamide/50 ml of chloroform.
3.88 g (18.79 mmol) of dicyclohexylcarbodiimide is added at 0°C,
and it is stirred for 1 hour at 0°C, then for 3 hours at room
temperature. It is cooled again to 0°C, and 5.19 g (51.27 mmol)
of triethylamine/50 ml of 2-propanol is added. Then, 10.78 g
(18.79 mmol) of the gadolinium complex of 10-(3-amino-2-hydroxy-
propyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
(WO 95/17451), dissolved in 50 mllof water, is added and stirred
for 3 hours at room terperature. It is evaporated to the dry
state, the residue is taken up in a mixture of 200 ml of
methanol/100 ml of chloroform, and dicyclohexylurea is filtered
out. The filtrate is evaporated to the dry state and purified by
RP-chromatography (RP-i8 mobile solvent: gradient consisting of
water/n-propanol/acetonitrile).
.
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Yield: 16.49 g (75% of theory) of a colorless, vitreous
solid
Water content: 6.5%
Elementary analysis:
Cld: C 33.95, H 3.18, N 6.99, S 2.67, F 26.85, Gd 13.07
Fnd: C 33.81 H 3.24, N 6.82, S 2.54, F 26.64 Gd 12.91
Esaatple 3 6
a) N-Decylperfluorooctanesulfonamide
50.21 g (100.0 mmol) of perfluorooctanesulfonyl fluoride is
added in drops to a mixture of 10.62 g (105.0 mmol) of
triethylamine and 15.73 g (100.0 mmol) of decylamine at 80°C
while being stirred vigorously. It is stirred for 2 days at
80°C, the reaction mixture is mixed with 300 ml of water and
extracted three times with ethyl acetate. The combined organic
extracts are dried on sodium sulfate, filtered and concentrated
by evaporation. The residue is chromatographed on silica gel
(mobile solvent: dichloromethane/methanol = 4/1).
Yield: 43.48 g (68% of theory) of a colorless, viscous
liquid
Elementary analysis:
Cld: C 33.81, H 3.47, N 2.19, S 5.02, F 50.51
Fnd: C 33.71 H 3.39, N 2.15, S 4.93, F 50.31
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b) N-Decyl-N-(perfluorooctylsulfonyl)-aminoacetic acid-t-butyl
ester
24.26 g (37.94 mmol) of the title compound of Example 36a
and 15.73 g (113.8 mmol) of potassium carbonate are suspended in
200 ml of acetone, and 14.80 g (75.87 mmol) of bromoacetic acid-
tert-butyl ester is added in drops at 60°C. It is stirred for 3
hours at 60°C. Salts are filtered out, and the filtrate is
evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
hexane/dichloromethane/acetone = 10/10/1). After the product-
containing fractions are concentrated by evaporation, the residue
is recrystallized from methanol/ether.
Yield: 24.87 g (87% of theory) of a waxy, colorless solid
Elementary analysis:
Cld: C 38.25, H 4.28, N 1.86, S 4.26, F 42.86
Fnd: C 38.09 H 4.41, N 1.74, S 4.10, F 42.67
c) N-Decyl-N-(perfluorooctylsulfonyl)-aminoacetic acid
20 g (26.54 mmol) of the title compound of Example 36b is
dissolved in 200 ml of trifluoroacetic acid and stirred overnight
at room temperature. It is evaporated to the dry state in a
vacuum. The residue is recrystallized from methanol/ether.
Yield: 17.22 g (93% of theory) of a colorless, crystalline
solid
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Elementary analysis:
Cld: C 34.44, H 3.47, N 2.01, S 4.60, F 46.31
Fnd: C 34.28 H 3.30, N 1.95, S 4.65, F 46.28
d) Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-aza-7-
(perfluorooctylsulfonyl)-heptadecyl]-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
11.92 g (17.09 mmol) of the title compound of Example 36c
and 1.97 g (18.79 mmol) of N-hydroxysuccinimide are dissolved in
a mixture of 50 ml of dimethylformamide/50 ml of chloroform.
3.88 g (18.79 mmol) of dicyclohexylcarbodiimide is added at 0°C,
and it is stirred for 1 hour at 0°C, then for 3 hours at room
temperature. It is cooled again to 0°C, and 5.19 g (51.27 mmol)
of triethylamine/50 ml of 2-propanol is added. Then, 10.78 g
(18.79 mmol) of the gadolinium complex of 10-(3-amino-2-hydroxy-
propyl)-1,4,7-tris(carbaxymethyl)-1,4,7,10-tetraazacyclododecane
(WO 95/17451), dissolved in 50 ml of water, is added, and it is
stirred for 3 hours at room temperature. It is evaporated to the
dry state, the residue is taken up in a mixture of 200 ml of
methanol/100 ml of chloroform, and dicyclohexylurea is filtered
out. The filtrate is evaporated to the dry state and purified by
RP-chromatography (RP-18 mobile solvent: gradient consisting of
water/n-propanol/acetonitrile).
Yield: 16.76 g (71$ of theory) of a colorless, vitreous
solid
Water content: 6.5%
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167
Elementary analysis:
Cld: C 35.46, H 4.18, N 6.71, S 2.56, F 25.77 Gd 12.55
Fnd: C 35.28 H 4.33, N 6.80 S 2.61, F 25.65 Gd 12.41
BZaaple 37
a) N-Hexylperfluorooctanesulfonamide
50.21 g (100.0 mmol) of perfluoroctanesulfonyl fluoride is
added in drops to a mixture of 10.62 g (105.0 mmol) of
triethylamine and 10.12 g (100.0 mmol) of benzylamine at 80°C
while being stirred vigorously. It is stirred for 2 days at
80°C, the reaction mixture is mixed with 300 ml of water and
extracted three times with ethyl acetate. The combined organic
extracts are dried on sodium sulfate, filtered and concentrated
by evaporation. The residue is chromatographed on silica gel
(mobile solvent: dichloromethane/methanol = 4/1).
Yield: 45.50 g (78% of theory) of a colorless liquid
Elementary analysis:
Cld: C 28.83, H 2.42, N 2.40, S 5.50, F 55.37
Fnd: C 28.29 H 2.39, N 2.44, S 5.55, F 55.50
b) N-Hexyl-N-(perfluorooctylsulfonyl)-aminoacetic acid-t-butyl
ester
22.13 g (37.94 mmol) of the title compound of Example 37a
and 15.73 g (113.8 mmol) of potassium carbonate are suspended in
200 ml of acetone, and 14.80 g (75.87 mmol) of bromoacetic acid-
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test-butyl ester is added in drops at 60°C. It is stirred for 3
hours at 60°C. Salts are filtered out, and the filtrate is
evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
hexane/dichloromethane/acetone = 10/10/1). After the product-
containing fractions are concentrated by evaporation, the residue
is recrystallized from methanol/ether.
Yield: 23.02 g (87% of theory) of a waxy, colorless solid
Elementary analysis:
Cld: C 34.44, H 3.47, N 2.01, S 4.60, F 46.31
Fnd: C 34.31 H 3.61, N 1.97, S 4.65, F 46.25
c) N-Hexyl-N-(perfluorooctylsulfonyl)-aminoacetic acid
20 g (28.43 mmol) of the title compound of Example 37b is
dissolved in 200 ml of trifluoroacetic acid, and it is stirred
overnight at room temperature. It is evaporated to the dry state
in a vacuum. The residue is recrystallized from methanol/ether.
Yield: 16.74 g (91% of theory) of a colorless, crystalline
solid
Elementary analysis:
Cld: C 29.96, H 2.51, N 2.18, S 5.00, F 50.36
Fnd: C 29.87 H 2.70, N 2.05, S 4.84, F 50.17
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d) Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-aza-7-
(perfluoraoctylsulfonyl)-tridecyl]-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
10.96 g (17.09 mmol) of the title compound of Example 37c
and 1.97 g (18.79 mmol) of N-hydroxysuccinimide are dissolved in
a mixture of 50 ml of dimethylformamide/50 ml of chloroform.
3.88 g (18.79 mmol) of dicyclohexylcarbodiimide is added at 0°C,
and it is stirred for 1 hour at 0°C, then for 3 hours at room
temperature. It is cooled again to 0°C, and 5.19 g (51.27 mmol)
of triethylamine/50 ml of 2-propanol is added. Then, 10.78 8
(18.79 mmol) of the gadolinium complex of l0-(3-amino-2-hydroxy-
propyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
(WO 95/17451), dissolved in 50 ml of water, is added, and it is
stirred for 3 hours at room temperature. It is evaporated to the
dry state, the residue is taken up in a mixture of 200 ml of
methanol/100 ml of chloroform, and dicyclohexylurea is filtered
out. The filtrate is evaporated to the dry state and purified by
RP-chromatography (RP-18 mobile solvent: gradient consisting of
water/n-propanol/acetonitrile).
Yield: 16.46 g (75% of theory) of a colorless, vitreous
solid
Water content: 6.8%
Elementary analysis:
Cld: C 33.11, H 3.70, N 7.02, S 2.68, F 26.98 Gd 13.14
Fnd: C 33.01 H 3.84, N 6.95, S 2.57, F 26.85 Gd 13.03
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$xampl~ 38
a) il-[N-Ethyl-N-(perfluorooctylsulfonyl)-amino]-hexanoic acid
benzyl ester
20 g (37.94 mmol) of N-ethyl-N-perfluorooctylsulfonylamide
and 15.73 g (113.8 mmol) of potassium carbonate are suspended in
200 ml of acetone, and 21.64 g (75.87 mmol) of 6-bromohexanoic
acid benzyl ester is added in drops at 60°C. It is stirred for 3
hours at 60°C. Salts are filtered out, and the filtrate is
evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
hexane/dichloromethane/acetone = 10/10/1). After the product-
containing fractions are concentrated by evaporation, the residue
is recrystallized from methanol/ether.
Yield: 25.26 g (91% of theory) of a colorless, crystalline
powder
Elementary analysis:
Cld: C 37.77, H 3.03, N 1.91, S 4.38, F 44.15
Fnd: C 37.61 H 3.18, N 1.84, S 4.27, F 44.01
b) il-[N-Ethyl-N-(perfluorooctylsulfonyl)-amino]-hexanoic acid
20 g (27.34 mmol) of the title compound of Example 38b is
dissolved in 300 ml of isopropanol/200 ml of dichloromethane, and
3 g of palladium catalyst (10% Pd/C) is added. It is
hydrogenated overnight at room temperature. Catalyst is filtered
out, and the filtrate is evaporated to the dry state in a vacuum.
The residue is recrysta~llized from ether/hexane.
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Yield: 16.13 g (92$ of theory) of a colorless, crystalline
solid
Elementary analysis:
Cld: C 29.96, H 2.51, N 2.18, S 5.00, F 50.36
Fnd: C 29.81 H 2.70, N 2.09, S 4.93, F 50.14
d) Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-11-aza-11-
(perfluorooctylsulfonyl)-tridecyl]-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
10.96 g (17.09 mmol) of the title compound of Example 38b
and 1.97 g (18.79 mmol) of N-hydroxysuccinimide are dissolved in
a mixture of 50 ml of dimethylformamide/50 ml of chloroform.
3.88 g (18.79 mmol) of dicyclohexylcarbodiimide is added at 0°C,
and it is stirred for 1 hour at 0°C, then for 3 hours at room
temperature. It is cooled again to 0°C, and 5.19 g (51.27 mmol)
of triethylamine/50 ml of 2-propanol is added. Then, 10.78 g
(18.79 mmol) of the gadolinium complex of 10-(3-amino-2-hydroxy-
propyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
(WO 95/17451), dissolved in 50 ml of water, is added, and it is
stirred for 3 hours at room temperature. It is evaporated to the
dry state, the residue is taken up in a mixture of 200 ml of
methanol/100 ml of chloroform, and dicyclohexylurea is filtered
out. The filtrate is evaporated to the dry state and purified by
RP-chromatography (RP-18 mobile solvent: gradient consisting of
water/n-propanol/acetonitrile).
f
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Yield: 15.0 g (69% of theory) of a colorless, vitreous
solid
Water content: 5.9%
Elementary analysis:
Cld: C 33.11, H 3.70, N 7.02, S 2.68, F 26.98 Gd 13.14
Fnd: C 33.01 H 3.83, N 6.91, S 2.49, F 26.83 Gd 13.05
E:ample 39
Blood Elimination Kinetics of Contrast Media
The blood elimination kinetics of contrast media was
examined in rats (Ban Wistar, Schering SPF, ~ 250 g of body
weight). For this purpose, after one-time intravenous
administration (via a caudal vein) of the substances (dose: 50-
100 ~Cmol of Me per kg of body weight), the substance
concentration in the blood (based on the Gd or Dy content) was
determined over a period of up to 300 minutes p.i. with the aid
of ICP-AES. The pharmacokinetic parameters: distribution volume
(Vss), total clearance (CLtot) and elimination half-life (tB)
were calculated with a special computer program (TOPFIT 2.0;
Thomae, Schering, Gc3decke), whereby a one- or two-compartment
distribution model was used as a basis.
In comparison to Dy-DTPA (the dysprosium analogue of
Magnevist~R~), the fluorine compounds according to the invention
(e. g., Example 1c) showed considerably slower elimination from
the blood and, in addition, a smaller distribution volume (see
also Figure 1 and Table 1).
r
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173
It has been determined, surprisingly enough, that these
compounds have an extended retention in the blood space and
therefore are suitable as "blood-pool contrast media" -- e.g.,
for the visualization of blood vessels with suitable
techniques -- even at relatively small dosages of S 50 ~.mol of Gd
per kg of body weight.
Figuro 1:
Elimination from the blood (in % of the injected dose) of
Dy-DTPA (dose: 100 ~,mol of Dy per kg of body weight, n = 3) and
of the fluorine compounds of Example lc according to the
invention (dose: 50 ~mol of Gd per kg of body weight, n = 2)
after one-time intravenous administration of substances in rats
(Han Wistar, Schering SPF, ~ 250 g of body weight).
The Gd and Dy contents in the blood were determined with the
aid of ICP-AES.
100.00%
'v 10.00%
0
O
c
:3
d 1.00%
~N
'C
d1
0.10%
0
0.01 %
0 3Q 60 90 120 150 180 Zlu cwu ~r~ ..JO
min p. i.
[Key to Table:]
% der injizierten Dosis = % of injected dose
Beispiel lc = Example lc
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174
Table 1:
Pharmacokinetic parameters: distribution volume (Vss), total
clearance (CLtot) and elimination half-life (tB) of Dy-DTPA and
the fluorine compounds of Example lc according to the invention
(calculated with TOPFIT 2.0; one- or two-compartment model).
Vss (1/kg) CLtot(ml/(min.kg)) tB (min)
MEAN SD MEAN SD MEAN SD
Dy-DTPA 0.17 0.00 9.27 0.60 14.98 0.73
Example 0.14 0.02 1.07 0.09 95.01 10.37
lc
For further details see text for Figure 1
8zample ~0
Lymph Node concentration in Guinaa Pigs
Various fluorine-containing gadolinium and manganese
complexes were examined 90 minutes to 24 hours after subcutaneous
administration (2.5-10 ~mol of total gadolinium/kg of body
weight, hind paw s.c.) to stimulated guinea pigs (complete
Freund's adjunct; 0.1 n1 i.m. respectively in the right and left
thigh and lower leg; 2 weeks before administration of test
substances) to determine their lymph node concentration in three
successive lymph node stations (popliteal, inguinal, iliac). In
this case, the results (determination of gadolinium concentration
with the aid of ICP-AES) that are listed below in Table 2 were
obtained:
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Tabl~ 2
Substance Time of Gadolinium
or manganese
concentration
in
Example lymph three successive
lymph node
stations
No. node
[~mol/1]
removal [% dose/g
of tissue]
(dose)
popliteal inguinal iliac ratio
1c) 4 h 120 ~Cmol/ 29 ~tmol/1 40 ~Smol/1 10:2.4:
(2.5 1 3.3
umol/kg) 17.2% 4.2% 5.6%
I
I
2c) 4 h 435 ~Cmol/ 84 ~mol/1 150 ~,mol/ 10:2.0:
(10 1 1 3.5
~mol/kg) 10.5% 2.0% 3.6% ~I
1e) 90 min 559 ~Cmol/ 224 ~mol/ 290 ~mol/ 10:4.0:
(10 1 1 1 5.2
~mol/kg) 15.0% 6.0% 7.8% I
3e) 90 min 880 ~Cmol/ 277 ~Cmol/ 339 ~mol/ 10:3.1:
(10 1 1 1 3.9
~mol/kg) 21.4% 6.7% 8.3%
Table 2 shows that a high contrast medium concentration
above three successive lymph node stations is to be noted.
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176
Example 41
Lymph node visualisation (MRT) after interstitial administration
of the contrast madius
Figure 1 shows MR recordings of popliteal and inguinal lymph
nodes both before (left side: precontrast) and 120 minutes after
(right side) subcutaneous administration (guinea pigs, hind paw,
interdigital space) of the Gd complex of Example 2c (referred to
in the figure as Gd-D03A-g-aminoamide-perfluorooctylether) (10
~cmol of Gd/kg of body weight). The T~-weighted spin echo
recordings (TR 400 ms, TE 15 ms) illustrate the. strong signal
rise in the popliteal and inguinal lymph nodes of the injected
side of the body (straight arrow) in comparison to the non-
injected side of the body (curved arrow), or to the precontrast
image.
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177
FIQUR$ l: MRT-Lymph Nod~ visusli$ation After Interstitial
Adniaistrat$on of th~ Coatrast Medium
[Key to Figure:]
MR-Bildgebung vor and nach interstitieller Applikation von 10
~mol Gd/kg = MR Imaging before and after interstitial
administration of 10 ~mol of Gd/kg
Gd-D03A-Y-aminoamid-perfluoroctylether = Gd-D03A-Y-aminoamide-
perfluorooctylether
Pr~kontrast = precontrast
T1-gewichtete Spin-Echo-Sequenz (TR 400/TE 15) Meerschweinchen,
Injektionsort: Zwischenzehenraum Hinterpfote (einseitig)
Pfeile: poplitealer and inguinal profunder Lymphknoten der
injizierten Seite = T'-weighted spin echo sequence (TR
400/TE 15) guinea pigs, injection site: interdigital space
of the hind paw (on one side); arrow: popliteally and
inguinally profound lymph nodes of the injected side
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178
Euampls 42
Elimination of the contrast Msdium after i.p. Administration
After administration of a perfluorinated gadolinium complex
according to the invention (100 ~mol of total gadolinium/kg of
body weight) in the intraperitoneal space of rats, the retention
of metal in the liver as well as in the remainder of the body was
examined 14 days after administration. In this test, fluorine-
containing compound 2c) was used. After 14 days p.i., the
gadolinium concentration was 0.22% of the administered dose in
the liver and 1.1% of the administered dose in the remainder of
the body.
In comparison with this, Gd-DPTA-polylysine as polymeric
material is not completely eliminated. After 14 days, the body
still contains 7% of the original dose.
Example 43
Determination of T'-Rslaxivity of Selected Compounds
The relaxivity of the following compounds was determined
with a Minispec pc 20 (20 MHz, 0.47T) at 37°C in water and human
plasma and compared to that of Gd-DTPA-polylysine and Magnevist~R~
as comparison substances.
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179
Table 3
Substance R'
Example No. [L/anol*sec]
at 0.47 T and 37C
peter Plasma
lc) 41 49
2c) 19 33
3c) 15.2 27.5
22f) 6.9 20.5
30c) 21.1 26.9
31c) 5.2 29.1
32C) 19.4 24.8
33f) 31.5 35.7
34b) 25.9 24.9
35d) 23.1 34.0
37d) 19.9 n.d.
38c) 23.3 30.5
Comparison subatancesa
Magnevist~R~ 3 . 8 4 . 8
Gd-DTPA-polylysine ~~ 13.1 16.8
n.d. ~ not determined
from Invest. Radiol. 1992, 346
