Note: Descriptions are shown in the official language in which they were submitted.
2102461
Process for the production of metal complexes of N-p-
hydroxyalkYl-tri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane
and N-S-hydroxyalkyl-tri-N-carboxyalkyl-1~4.8,11-
tetraazacyclotetradecane derivatives
The invention relates to the process for the production of
metal complexes, characterized in the claims, of N-~-
hydroxyalkyl-tri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane
and N-J3-hydroxyalkyl-tri-N-carboxyalkyl-1,4,8,11-
tetraazacyclotetradecane derivatives.
Because of their importance as imaging diagnostic agents (DE
OS 36 25 417), especially NMR diagnostic agents, the production
of metal complexes of N-/3-hydroxyalkyl-tri-N-carboxyalkyl-
1,4,7,10-tetraazacyclododecane and N-Q-hydroxyalkyl-tri-N-
carboxyalkyl-1,4,8,11-tetraazacyclotetradecane derivatives has
been tried in varied ways without a satisfactory method of
synthesis, especially for their production on an industrial
scale, previously having been able to be found.
In German laid-open specification DE 36 25 417 A1 a process
for the production of metal complexes of N substituted tri-N-
carboxyalkyl-1,4,7,10-tetraazacyclododecane derivatives is
described, in which tri-N-ethoxycarbonyimethyl-1,4,7,10-
tetraazacyclododecane derivatives, that have a substitutent on
the fourth nitrogen atom, are converted after cleavage of the
_ still present carboxy protective groups into the metal complexes.
The cyclic initial material needed for this process is obtained
by specific ring synthesis. Thus a start is made from two
2
reactants, which are cyclized according to methods known from the
literature [e. g., Richman, Org. Synthesis 58, 86 (1978); Atkins,
J. Amer. Chem. Soc. 96, 2268 (1974)J; one of the two reactants
contains a protected nitrogen atom and carries on the chain end
two leaving groups (e. g., bromine, mesyloxy, tosyloxy, triflate
or alkoxycarbonyl groups) that is nucleophilically displaced from
the terminal nitrogen atoms of the second reactant of a --
different from the first reactant -- protected triaza compound.
The protective group chemistry used in the process of DE 36
25 417 A1 always leads to additional reaction steps in which the
protective group must be removed again. Further large amounts of
salts accumulate in the cleavage that then must be disposed of.
Therefore an avoidance of protective groups, especially for a
process that is to be used on an industrial scale, is desirable.
Tweedle et al. describe in European patent application 292
689 A7 and in publication Inorg. Chem. 1991, 30, 1265-1269 that
starting from the unsubstituted macrocyclic compound 1,4,7,10-
tetraazacyclododecane, the N-formyl compound can be obtained by a
- tricyclic intermediate stage. This compound still carrying three
unprotected nitrogen atoms can now be trialkylated, deformylated
and converted to the tetrasubstituted tetraazamacrocycle with
haloacetic ester derivatives. After cleavage of the carboxy
protective groups the tetrasubstituted complexing agent is
obtained that can be reacted to the complex.
The synthesis method for the metal complexes described by
Tweedle et al. for N substituted tri-N-carboxyalkyl-1,4,7,10-
tetraazacyclododecane derivatives has not only the disadvantage
2102461
of an unsatisfactorily high number of steps but it is not very
' ' suitable because of the high expenses for purification of the
intermediate steps and high costs for large amounts of ion
exchangers necessary for the production on an industrial scale.
Further although a reaction of tri-N-carboxymethyl-1,4,7,10-
tetraazacyclododecane (D03A, compound (2) in Inorg. Chem. Vol.
30, No. 6, 1991, 1267) with primary epoxides is possible,
however, the yields for the reaction with secondary epoxides are
clearly inferior and poorly suitable for use on an industrial
scale.
Therefore it continues to be the object to make available a
process for the production of metal complexes of N-,Q-
hydroxyalkyl-tri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane
and N-~-hydroxyalkyl-tri-N-carboxyalkyl-1,4,8,11-
tetraazacyclotetradecane derivatives, that as much as possible
does not restrict the selection of the electrophiles needed in
the process for the reaction and that above all is suitable for
the reaction of sizable amounts of substance.
- This object is achieved by this process.
It was found that the production of metal complexes of N-f~-
hydroxyalkyl-tri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane
and. N-R-hydroxyalkyl-tri-N-carboxyalkyl-1,4,8,11-
tetraazacyclotetradecane derivatives of general formula I
. ... . _
4
~loz4sl
1
_ R
~N N
C
~ J, z
R
R (CH )
in
in which
R~ means -CH2-COOY
Y means hydrogen, a metal ion equivalent of an element of
atomic numbers 21-32, 37-39, 42-51 or 57-83 provided that at
least two substituents Y stand for metal equivalents
n means the numbers 2 or 3
OH
s
Rz means a ~4 -CH-R group
R
R4 and R5, independent of one another, each stand for a
hydrogen atom, a C~-C2o alkyl radical optionally interrupted by 1
to 10 oxygen atom or atoms, a phenylene, phenylenoxy or
phenylenedioxy group, which is optionally substituted by 1 to 3
C~-C6 alkyl, 1 to 3 trifluoromethyl, 1 to 7 hydroxy, 1 to 3 Ci-C7
- alkoxy or aralkoxy, 1 to 2 COZR6 radicals,
in which R6 stands for a hydrogen atom, a Ci-Cb alkyl
group, a C6-Coo aryl or a C6-Cio-Ar(C~-C4)alkyl group,
and/or 1 to 2 phenoxy or phenyl groups optionally substituted by
1 to 2 chloro, bromo, nitro or C~-Cb alkoxy radicals,
and the optionally present hydroxy radicals optionally are
present in protected form,
2102461
- characterized in that the compound obtained from 1,4,7,10-
' ' tetraazacyclododecane or 1,4,8,11-tetraazacyclotetradecane of
general formula II
,
zn
- N-..'
Zn
(II)
in which
n stands for the numbers 2 or 3
is reacted with an epoxide of general formula III
0
R4.~Ra
(III),
in which
R4 and R5 have the above-indicated meanings, and optionally
present hydroxy or carboxy groups are optionally protected, to a
- intermediate of general formula IV
(CH2)~
N
N
z
R
~ (~H , J
2 n (IV~~
in which
R2 has the above-indicated meaning,
6 210241
- and optionally present hydroxy groups and/or carboxy groups are
optionally protected,
the latter is saponified to an intermediate V
H\ ' (CH2)~ \ /H
N( 1N
N
ERs
(CH )
- =n
and the latter is reacted in the presence of a base with a
compound of formula VI
X-CHZ-COOZ (VI),
in which
X means a leaving group
Z means hydrogen, a carboxy protective group or a metal
cation
optionally after protection of hydroxy or carboxy groups in
- a polar solvent at -10°C to 170°C within 1-100 hours, the
protecting groups are optionally cleaved off and the thus
obtained complexing agent of formula VII
{CH2)n~~C00H
HOOC l~~
N
_ C N~
- - ~~ J~ z
HOOC {CH ) R
zn
(VII)
7 2~o24s 1
- is reacted with a metal oxide or metal salt of an element of
atomic numbers 21-32, 37-39, 42-51 or 57-83 and optionally still
present hydrogen atoms are also substituted by cations of
inorganic and/or organic bases, amino acids or amino acid amides
or the still present acid groups are converted completely or
partially into esters or amides.
The process according to the invention shows the following
surprising effects:
1) The desired metal complexes of general formula (I) are
obtained in a "one-pot reaction" under favorable operating
conditions in higher yield than in the process of the prior art.
2) The intermediates are obtained in a so surprising high
purity that their isolation and purification can be dispensed
with.
3) In contrast with the process according to Tweedle et al.
the reaction takes place with good yields even with secondary
epoxides.
4) In comparison with the prior art, the process according
- to the invention comprises fewer steps.
5) The use of protective groups is indeed possible but not
necessary for the process according to the invention.
A process is preferred that is characterized in that a
compound of formula (I)
(CH )
_ _ R' ( 2 n ~/R
N
J,Rz
R (CH )
Zn
m
8
2102461
- in which
' ' R~ means -CHZ-COOY
Y means a metal ion equivalent of an element of atomic
numbers 21-32, 37-39, 42-51 or 57-83 provided that at least two
substituents Y stand for metal equivalents
n means the number 2
off
R2 means a CH-CH-RS group
~4
R
R4 and RS, independent of one another, each stand for a
hydrogen atom, a C~-Coo alkyl radical optionally interrupted by 1
to 5 oxygen atom or atoms, a phenylene, phenylenoxy or
phenylenedioxy group, which optionally is substituted by l to 3
Ci-C6 alkyl, 1 to 3 trifiuoromethyl, 1 to 5 hydroxy, 1 to 3
alkoxy or 1 to 2 C02R6 radicals,
and/or l to 2 phenoxy or phenyl groups optionally
substituted by a nitro group or a C~-C6 alkoxy radical and
R6 stands for a hydrogen atom, a C~-C6 alkyl group or a
- benzyl group, is reacted.
Especially preferred is a process for the production of
metal complexes of 10-(1-hydroxymethyl-2,3-dihydroxypropyl)-
1,4;7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane and of
metal complexes of 10-(2-hydroxypropyl)-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane.
Quite especially preferred is a process for the production
of gadolinium or dysprosium complexes of 10-(1-hydroxymethyl-2,3-
dihydroxypropyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-
210241
. tetraazacyclododecane and gadolinium or dysprosium complexes of
10-(2-hydroxypropyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane.
Preferred radicals R4 and R5 are the hydrogen atom, the
methyl, ethyl, 2-hydroxyethyl, 2-hydroxy-1-(hydroxymethyl)ethyl,
1-(hydroxymethyl)ethyl, propyl, isopropyl, isopropenyl, 2-
hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, butyl,
_ isobutyl, isobutenyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-
hydroxybutyl, 2-hydroxy-2-methylbutyl, 3-hydroxy-2-methylbutyl,
4-hydroxy-2-methylbutyl, 2-hydroxyisobutyl, 3-hydroxyisobutyl,
2,3,4-trihydroxybutyl, 1,2,4-trihydroxybutyl, pentyl,
cyclopentyl, 2-methoxyethyl, hexyl, decyl, tetradecyl,
triethylene glycol methyl ether, tetraethylene glycol methyl
ether and methoxybenzyl group as well as the
-CH2-O-Ct >HZZ-OH-,
-CH2-O-C6H4-O- ( CHZCHZO ) 2-CH3-,
-CH2-O-C6H4-O- { CHZCH20 ) 3-C5H> >-,
._ -CHZ-O-C6H4-O-C4H$-OH- ,
' - ( CH2CH20 ) S-CH3-,
-C9H~$-COON-,
-C9H~$-OH-,
-CH2-O-C6H4-O-C6H~z-COON-,
-CHZ-O-C6H4-O-C4H8-O-CHZ-CHOH-CH20H- ,
- ( CHZCHZ-O ) 3-CSH1 ~ - ,
-CH2-O-C~ oH2o-COOH- ,
-CH2-O-C6H4-C1-,
-CH2-O-C6H4-NOz- ,
10
zloz~~1
-CHz-O-C6H3C12-,
-CH2-O-C6H4-O-CHZ-COON- ,
-CH2-O-C6H4-O-CH2-COON- and
-CHZ-O-C6H4-CSH> > group .
As alkoxy substituents in R4 and R5 are meant straight chain
or branched radicals with 1 to 6 or 1 to 7 C atoms such as, for
example, methoxy, ethoxy, propoxy, isopropoxy.
As alkyl groups R6 with 1-6 carbon atoms, straight chain or
branched alkyl groups are suitable such as, for example, methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl.
Especially preferred are methyl, ethyl, tert.-butyl.
Preferred aryl groups and aralkyl groups R6 are phenyl,
naphthyl and benzyl groups.
Especially preferred radicals R6 are hydrogen, the methyl
radical or benzyl radical.
The tetraazatricyclotridecanes or pentadecanes of general
formula II used as feedstocks are available according to methods
known from the literature, in that 1,4,7,10-tetraazacyclododecane
or 1,4,8,11-tetraazacyclotetradecane is reacted with
dimethylformamide dimethylacetal (US patents 4,085,106 and
4,130,715).
Advantageously this reaction step is included in the process
according to the invention.
Reaction conditions for the process steps
1) (II) + (III) 1 (IV) -~ (V)
The reaction of the tricyclic intermediate step (II) with an
epoxide of formula (III) takes place with or without solvent
CA 02102461 2004-O1-12
11
between 0°C and 220°C, preferably between room temperature and
120°C, within 1 to 48 hours, preferably from 5 to 12 hours,
optionally at a pressure of up to 100 atm.
The reaction mixture containing compound (IV), after cooling
to -20°C to 80°C, preferably 0°C to 30°C, is mixed
with a mixture
of water/organic solvent, and stirred 0.5 to 12 hours, preferably
0.5 to 3 hours at -20°C to room temperature, preferably 0°C to
room temperature.
By addition of an inorganic base or an acid at 0°C to
150°C,
preferably room temperature to 120°C, within 1 to 72, preferably
6 to 24 hours, with stirring -- optionally followed by subsequent
protective group removal in a manner usual in the art - - is
reacted to the intermediate of formula V. The latter can also be
isolated, if desired, as salt, preferably as hydrochloride.
As solvents for the reaction of the compounds of formula II
with compounds of formula III, above all aprotic solvents such
as, for example, benzene, tolene, dichloromethane,
tetrahydrofuran, dioxane, acetonitrile, dimethylformamide,
dimethylacetamide, dimethylsulfoxide, hexane or diethylether are
suitable.
The solvents used in the mixture with water can be, e.g.,
methanol, ethanol, isopropanol, tetrahydrofuran, dioxane.
As base or acid, for example, alkali and alkaline-earth
hydroxides, alkali and alkaline-earth carbonates or mineral acids
such as, e.g., hydrochloric acid or sulfuric acid or methane
sulfonic acid are suitable.
12
2~o24s~
2) (V) + (VI) -~ (VII)
The bases added as acid traps in the further reaction of the
intermediate of formula V with a compound of formula VI can be
tertiary amines (e. g., triethylamine, trimethylamine, N,N-
dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]-non-5-ene (DBN),
1,5-diazabicyclo[5.4.0]-undec-5-ene (DBU), alkali or alkaline-
earth carbonates, alkali or alkaline-earth bicarbonates, or
alkali or alkaline-earth hydroxides (e.g., lithium-, sodium-,
magnesium-, calcium-, barium-, potassium-, -carbonate, -hydroxide
and -bicarbonate).
The reaction takes place in polar solvents such as, for
example, water, acetonitrile, dimethylformamide,
dimethylsulfoxide, hexamethylphosphoric acid triamide or
tetrahydrofuran as well as in alcohols with a chain length with
up to 8 C atoms such as, e.g., methanol, ethanol, propanol,
isopropanol, n-butanol, isobutanol, tert.-butanol.
The reaction is performed at temperatures of -10°C-170°C,
preferably at 0°-120°C, especially preferred at 40°-
100°C, within
0.5-48 hours, preferably 3-24 hours.
The optionally performed introduction or cleavage of
protective groups of carboxyl- or hydroxy functions takes place
according to methods known in the literature.
As acid protective groups lower alkyl-, aryl- and aralkyl
groups, for example, methyl-, ethyl-, propyl-, n-butyl-, tert.-
butyl-, phenyl-, benzyl-, diphenylmethyl-,
triphenylmethyl-, bis(p-nitrophenyl)-methyl groups, as well as
trialkylsilyl groups are suitable.
13
2ZOZ4s~
The cleavage of the protective groups takes place according
to processes known to one skilled in the art, for example, by
hydrolysis, hydrogenolysis, alkaline saponification of the esters
with alkali in aqueous alcoholic solution at temperatures of 0 to
50°C, acid saponification with mineral acids or in the case of
e.g., tert.-butyl esters with the help of trifluoroacetic acid.
As metal cations Z, metal cations of the elements of alkali or
alkaline-earth metals are possible.
As hydroxy protective groups, e.g., benzyl-, 4-
methoxybenzyl-, 4-nitrobenzyl-, trityl-, diphenylmethyl-,
trimethylsilyl-, dimethyl-t-butylsilyl-, diphenyl-t-butylsilyl
groups are suitable.
The hydroxy groups can also be present e.g., as THP-ether,
a-alkoxyethylether, MEM-ether or as the esters with aromatic or
aliphatic carboxylic acids, such as, e.g., acetic acid or benzoic
acid. In the case of polyols, the hydroxy groups can also be
protected in the form of ketals with, e.g., acetone,
acetaldehyde, cyclohexanone or benzaldehyde.
- The hydroxy protective groups can be released according to
methods known from the literature to one skilled in the art,
e.g., by hydrogenolysis, reductive cleavage with lithium/ammonia,
acid treatment of the ethers and ketals or alkali treatment of
the esters (see, e.g., "Protective Groups in Organic Synthetics",
T.W. Greene, John Wiley and Sons 1981).
The intermediately obtained complexing agents of formula VII
can be purified in an advantageous way by ion exchangers. For
this purpose especially cation exchangers (in the H+ form) which
14
_ . 2102461
are first washed with water and then, eluted with aqueous ammonia
solution, yield the desired product. IR 120 (H') and AMB 252c
(H') as well as Reillex~ have proven to be especially
advantageous exchangers. If Reillex~ is used the complexing
agent is eluted with water or aqueous alcohols.
3) (VII) --~ (I)
The production of the metal complexes according to formula I
takes place in a way known in the art by the complexing agents of
general formula VII being reacted with a metal oxide or metal
salt of an element of atomic numbers 21-32, 37-39, 42-51 or 57-83
preferably in water and/or in aqueous solutions of lower alcohols
(such as, e.g., methanol, ethanol or isopropanol) at temperatures
of 20°C-110°C, preferably 80°C-100°C. The addition
of 0.1-4
equivalents, preferably 0.5-2 equivalents, of an inorganic or
organic acid, preferably acetic acid, has proved to be especially
advantageous.
The thus obtained metal complex solutions can advantageously
be purified by treatment on an ion exchange cascade or in a
batch, consisting of an acid cation exchanger (H+ form) and basic
anion exchanger (OH' form), preferably IR 120 H+, AMB 252c/IRA
67.
The final cleaning is performed by crystallization from a
lower alcohol, or an alcohol-water mixture. As alcohols there
can be mentioned methanol, isopropanol, however ethanol is
preferred.
15
.. 21Q2461
The metal salts used can be, for example, nitrates,
acetates, carbonates, chlorides or sulfates. The metals
contained in the metal oxide or metal salt used can be an element
of atomic numbers 21-32, 37-39, 42-51 or 57-83.
The following examples are used for detailed explanation of
the object of the invention, however they are not to limit it.
Example 1
Gadolinium complex of 10-(1-hydroxymethyl-2,3-dihydroxypropyl)-
1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
a) 20 1 (150.55 mol) of dimethylformamide dimethyl acetal
is added (under nitrogen) to 20 kg (116.10 mol) of cyclene
(=1,4,7,10-tetraazacyclododecane) in 140 1 of toluene. It is
slowly heated up and the azeotrope is distilled off from
methanol/dimethylamine/toluene. Then, the solvent is completely
distilled off by applying a vacuum. The remaining oil is allowed
to cool to 50°C and then 18.7 kg (about 95%) (123.22 mol) of 4,4-
dimethyl-3,5,8-trioxabicyclo-(5.1.0)-octane is instilled (under
" nitrogen). Then, it is stirred for 24 hours at 120"C. It is
- cooled to room temperature and a mixture of 100 1 of water/150 1
of methanol is instilled. Then, it is stirred for 1 hour at 50°C
and 13.93 kg (348.3 mol) of sodium hydroxide is added. Then, it
is refluxed for 8 hours. The solution is substantially
evaporated to dryness, 200 1 of water is added and again about
100 1 of water is distilled off. Again, 100 1 of water is added
and this solution is extracted once with 200 1 of n-butanol and
then with 50 1 of n-butanol. The combined butanol phases are
evaporated to dryness in a vacuum and the residue is taken up in
16
21p2461
- 300 1 of water. Then, it is extracted twice with 50 1 of ethyl
acetate each. The water phase is separated and concentrated by
evaporation to a volume of about 200 1.
b) 43.84 kg (464.4 mol) of chloroacetic acid is dissolved
in 150 1 of water and adjusted to pH 7 with 50% aqueous sodium
hydroxide solution. The water phase concentrated by evaporation
to a volume of about 200 1 is added to this solution and heated
_ to 80°C. The pH is kept between pH 9.5 - 10 by adding 50%
aqueous sodium hydroxide solution. After 10 hours, another 10.96
kg (116.1 mol) of chloroacetic acid (previously neutralized as
described above in 35 1 of water with 50% aqueous sodium
hydroxide solution) is added. It is stirred for 12 hours at 80°C
and the pH is kept between 9.5 and 10. It is allowed to cool to
room temperature and adjusted with concentrated hydrochloric acid
to pH 0.8. Then, it is stirred for 2 hours at 60°C. The
solution is substantially evaporated to dryness in a vacuum. The
residue is mixed twice with a mixture of 200 1 of methanol/200 1
of ethanol and evaporated to dryness. Then, the residue is
- absorptively precipitated for 1 hour at 50°C with 400 1 of
methanol. It is filtered off from the precipitated sodium
chloride, rewashed twice with 100 1 of methanol and the combined
filtrates are evaporated to dryness in a vacuum. The residue is
dissolved in 200 1 of water and added to an ion exchange column,
filled with AMB 252c. It is washed with ample water and the
product is eluted with a 10% aqueous ammonia solution. The
product-containing fractions are substantially evaporated to
dryness in a vacuum.
17
2102461
c) The residue is dissolved in 200 1 of water and 16.31 kg
(45 mol) of gadolinium oxide is added. It is refluxed for 3
hours. Then,-2 1 of glacial acetic acid is added and refluxed
for another 2 hours. 5 kg of activated carbon is added and
stirred for 1 hour at 90°C. The solution is filtered and the
filtrate is added several times on an ion exchange column cascade
(consisting of IRA 67 (OH- form)) AMB 252c (H~ form) (under HPLC
control). The eluate is concentrated by evaporation to a volume
of 300 1 and stirred for 3 hours with 2 1 of acid ion exchanger
IR 120 (H+) as well as basic exchanger IRA 67 (OH~) each. It is
filtered off from the exchanger and rewashed twice with 10 1 of
water. 5 kg of activated carbon is added to the filtrate and
stirred for 2 hours at 80°C. The solution is filtered and the
filtrate is concentrated by evaporation in a vacuum. The residue
is recrystallized from 95% aqueous ethanol (about 400 1). The
precipitate is suctioned off, rewashed twice with 80 1 of pure
ethanol and dried for 48 hours at 70°C in a drying oven.
Yield: 47.6 kg (65.0% of theory) (corrected for water/
relative to cyclene) of colorless crystalline powder
Water content: 4.1%
Elementary analysis (relative to the anhydrous substance):
Cld: C 35.75 H 5.17 N 9.27 Gd 26.00
Fnd: C 35.92 H 5.24 N 9.20 Gd 25.83
18
202461
Example 2
Dysprosium complex of 10-[1-hydroxymethyl-2,3-dihydroxypropyl]-
1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
Analogously, the corresponding dysprosium complex can be
produced if, instead of gadolinium oxide, correspondingly 16.78
kg (45 mol) of dysprosium oxide is reacted.
Yield: 46.36 kg (62.7% of theory) (corrected for
water/relative to cyclene)
Water content: 3.9%
Elementary analysis (relative to the anhydrous substance):
Cld: C 35.44 H 5.12 N 9.19 Dy 26.64
Fnd: C 35.35 H 5.21 N 9.11 Dy 26.57
Example 3
Gadolinium complex of 10-(2-hydroxypropyl)-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
a) 20 1 (150.55 mol) of dimethylformamide dimethyl acetal
is added (under nitrogen) to 20 kg (116.10 mol) of cyclene
~ (=1,4,7,10-tetraazacyclododecane) in 140 1 of toluene. It is
slowly heated up and the azeotrope is distilled off from
methanol/dimethylamine/toluene. Then, the solvent is completely
distilled off by applying a vacuum. The remaining oil is allowed
to cool to 50°C and then 10.11 kg (174.15 mol) of propylene oxide
is instilled (under nitrogen). Then, it is refluxed for 24 hours
and then excess propylene oxide is distilled off in a vacuum. It
is cooled to room temperature and a mixture of 100 1 of water/150
1 of methanol is instilled. Then, it is stirred for 1 hour at
19
., 2~o24s~
50°C and 13.93 kg (348.3 mol) of sodium hydroxide is added.
' ' Then, it is refluxed for 8 hours. The solution is substantially
evaporated to dryness, 200 1 of water is added and again about
100 1 of water is distilled off. 100 1 of water is again added,
and this solution is extracted once with 200 1 of n-butanol and
then with 100 1 of n-butanol. The combined butanol phases are
evaporated to dryness in a vacuum and the residue is taken up in
300 1 of water. Then, it is extracted twice with 50 1 of ethyl
acetate each. The water phase is separated and concentrated by
evaporation to a volume of about 200 1.
b) 43.84 kg (464.4 mol) of chloroacetic acid is dissolved
in 150 1 of water and adjusted to pH 7 with 50% aqueous sodium
hydroxide solution. The water phase concentrated by evaporation
to a volume of about 200 1 is added to this solution and heated
to 80°C. The pH is kept between pH 9.5 - 10 by adding 50%
aqueous sodium hydroxide solution. After 10 hours, another 10.96
kg (116.1 mol) of chloroacetic acid (previously neutralized as
described above in 35 1 of water with 50% aqueous sodium
- hydroxide solution) is added. It is stirred for 12 hours at 80°C
and the pH is kept between 9.5 and 10. It is allowed to cool to
room temperature and adjusted with concentrated hydrochloric acid
to pH 0.8. The solution is substantially evaporated to dryness
in a vacuum. The residue is mixed twice with a mixture of 200 1
of methanol/200 1 of ethanol and evaporated to dryness. Then,
the residue is absorptively precipitated for 1 hour at 50°C with
400 1 of methanol. It is filtered off from the precipitated
sodium chloride, rewashed twice with 100 1 of methanol and the
20
2I024fi1
combined filtrates are evaporated to dryness in a vacuum. The
' ' residue is dissolved in 200 1 of water and added to an ion
exchange column, filled with AMB 252c. It is washed with ample
water and the product is eluted with a 10% aqueous ammonia
solution. The product-containing fractions are substantially
evaporated to dryness in a vacuum.
c) The residue is dissolved in 200 1 of water and 17.62 kg
(48.6 mol) of gadolinium oxide is added. It is refluxed for 3
hours. Then, 2 1 of glacial acetic acid is added and refluxed
for another 2 hours. 5 kg of activated carbon is added and
stirred for 1 hour at 90°C. The solution is filtered and the
filtrate is added several times by an ion exchange column cascade
(consisting of IRA 67 (OH- form)) of AMB 252c (H' form) (under
HPLC control). The eluate is concentrated by evaporation to a
volume of 300 1 and stirred for 3 hours with 2 1 of acid ion
exchanger IR 120 (H+) as well as basic exchanger IRA 67 (OH-)
each. It is filtered off from the exchanger and rewashed twice
with 10 1 of water. 5 kg of activated carbon is added to the
- filtrate and stirred for 2 hours at 80°C. The solution is
filtered and the filtrate is concentrated by evaporation in a
vacuum. The residue is recrystallized from ethanol {about 300
1). The precipitate is suctioned off, rewashed once with 50 1 of
pure ethanol and dried for 48 hours at 70°C in a drying oven.
Yield: 45.22 kg {67.2 of theory) (corrected for
water/relative to cyclene) of colorless crystalline powder
Water content: 3.5~
Elementary analysis (relative to the anhydrous substance):
21
2~0~~.~1
' Cld: C 36.55 H 5.23 N 10.03 Gd 28.15
Fnd: C 36.68 H 5.31 N 9.91 Gd 28.03
Example 4
Dysprosium complex of 10-(2-hydroxypropyl)-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
Analogous to example 3c), the corresponding dysprosium
complex can be produced, if, instead of gadolinium oxide,
correspondingly 18.13 kg (48.6 mol) of dysprosium oxide is
reacted.
Yield: 47.14 kg (65.3% of theory) (corrected for
water/relative to cyclene)
Water content: 4.1%
Elementary analysis (relative to the anhydrous substance):
Cld: C 36.20 H 5.18 N 9.94 Dy 28.82
Fnd: C 36.32 H 5.27 N 9.87 Dy 28.69
Example 5
- Gadolinium complex of l0-(2-hydroxy-3-methoxy-propyl)-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
Analogously it can be reacted with 2,3-
epoxypropylmethylether instead of propylene oxide as described in
example 3. Thus, for example, 216.7 g (61% of theory) of the
title compound is obtained from 100 g (0.58 mol) of 1,4,7,10-
tetraazacyclododecane as colorless powder (crystallization from
aqueous acetone).
Water content: 3.8%
22
210201
Elementary analysis (relative to the anhydrous substance):
' ' Cld: C 36.72 H 5.72 N 9.52 Gd 26.71
Fnd: C 36.51 H 5.83 N 9.39 Gd 26.57
Example 6
Gadolinium complex of 10-(2-hydroxy-3-benzyloxy-propyl)-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
Analogously it can be reacted with 2,3-epoxypropyl-
benzylether instead of propylene oxide as described in example 3.
1.1 equivalents of epoxide is used relative to 1,4,7,10-
tetraazacyclododecane. It is heated for 16 hours at 110°C
(instead of 24 hours as described in example 3). Thus 249.2 g
(62% of theory) of the title compound is obtained from 100 g
(0.58 mol) of 1,4,7,10-tetraazacyclododecane (crystallization
from isopropanol).
Water content: 4.2%
Elementary analysis (relative to the anhydrous substance):
Cld: C 43.36 H 5.31 N 8.43 Gd 23.65
- Fnd: C 43.21 H 5.40 N 8.32 Gd 23.48
Example 7
Gadolinium complex of 10-(2,3,4-trihydroxybutyl)-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
Analogously it can be reacted with 2-(2,2-dimethyl-1,3-
dioxolan-4-yl)-ethylene oxide instead of 4,4-dimethyl-3,5,8-
trioxabicyclo-(5.1.0)-octane as described in example 1. 1.1
equivalents of epoxide is used relative to 1,4,7,10-
23
~10~461
tetraazacyclododecane. It is heated for 16 hours at 110°C
' ' (instead of 24 hours as described in example 1). Thus 232.8 g
(64% of theory) of the title compound is obtained as colorless,
crystalline powder from 100 g (0.58 mol) of 1,4,7,10-
tetraazacyclododecane (crystallization from 90% aqueous ethanol).
Water content: 3.5%
Elementary analysis (relative to the anhydrous substance):
Cld: C 35.75 H 5.17 N 9.26 Gd 26.00
Fnd: C 35.55 H 5.23 N 9.14 Gd 25.87
Example s
Gadolinium complex of 10-(2-hydroxy-3-tert.-butoxy-propyl)-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
Analogously it can be reacted with 2,3-epoxypropyl-tert.-
butyl ester instead of propylene oxide as described in example 3.
1.1 equivalents of epoxide is used relative to 1,4,7,10-
tetraazacyclododecane. It is heated for 16 hours at 110°C
-a (instead of 24 hours as described in example 3). Thus 225 g (59%
- of theory) of the title compound is obtained as colorless,
crystalline powder from 100 g (0.58 mol) of 1,4,7,10-
tetraazacyclododecane (crystallization from acetone/ethanol).
Water content: 4.0%
Elementary analysis (relative to the anhydrous substance):
Cld: C 39.99 H 5.91 N 8.88 Gd 24.93
Fnd: C 39.81 H 6.05 N 8.73 Gd 24.82
24
w . 2~p24G1
Example 9
' ' Gadolinium complex of 10-(2,6,7-trihydroxy-4-oxaheptyl)-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
Analogously it can be reacted with 2,2-dimethyl-4-(2',3'-
epoxy)-propoxy-methyl-1,3-dioxolane instead of 4,4-dimethyl-
3,5,8-trioxabicyclo-(5.1.0)-octane as described in example 1.
1.1 equivalents of epoxide is used relative to 1,4,7,10-
tetraazacyclododecane. It is heated for 16 hours at 110°C
(instead of 24 hours as described in example 1). Thus 242.2 g
(62% of theory) of the title compound is obtained as colorless,
crystalline powder from 300 g (0.58 mol) of 1,4,7,10-
tetraazacyclododecane (crystallization from ethanol).
Water content: 3.6%
Elementary analysis (relative to the anhydrous substance):
Cld: C 37.03 H 5.44 N 8.64 Gd 24.24
Fnd: C 36.91 H 5.58 N 8.49 Gd 24.13
Example io
- Gadolinium complex of 10-(2-hydroxy-3-isopropoxy-propyl)-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
Analogously it can be reacted with 2,3-epoxypropylisopropyl
ether instead of propylene oxide as described in example 3. 1.1
equivalents of epoxide is used relative to 1,4,7,10-
tetraazacyclododecane. It is heated for 16 hours at 110°C
(instead of 24 hours as described in example 3). Thus 232.5 g
(63% of theory) of the title compound is obtained as colorless,
25
21U'~~61
crystalline powder from 100 g {0.58 mol) of 1,4,7,10-
' ' tetraazacyclododecane (crystallization from isopropanol).
Water content: 3.1%
Elementary analysis (relative to the anhydrous substance):
Cld: C 38.95 H 5.72 N 9.08 Gd 25.50
Fnd: C 38.85 H 5.81 N 8.93 Gd 25.35
Example il
Gadolinium complex of 10-(2-hydroxy-2-methyl-propyl)-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
Analogously it can be reacted with iso-butylene oxide
instead of propylene oxide as described in example 3. Thus for
example 209.4 g (60% of theory) of the title compound is obtained
as colorless powder from 100 g {0.58 mol) of 1,4,7,10-
tetraazacyclododecane (crystallization from aqueous acetone).
Water content: 4.0%
Elementary analysis (relative to the anhydrous substance):
Cld: C 37.75 H 5.46 N 9.78 Gd 27.46
~ Fnd: C 37.61 H 5.53 N 9.70 Gd 27.38
Example 12
Gadolinium complex of 10-{2-hydroxy-3-phenoxy-propyl)-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
Analogously it can be reacted with 2,3-epoxypropyl-phenyl
ether instead of propylene oxide as described in example 3. 1.1
equivalents of epoxide is used relative to 1,4,7,10-
tetraazacyclododecane. It is heated for 16 hours at 110°C
26
(instead of 24 hours as described in example 3). Thus 252.4 g
' ' (64% of theory) of the title compound is obtained as colorless,
crystalline powder from 100 g (0.58 mol) of 1,4,7,10-
tetraazacyclododecane (crystallization from aqueous acetone).
Water content: 3.7%
Elementary analysis (relative to the anhydrous substance):
Cld: C 43.49 H 5.02 N 8.45 Gd 23.73
Fnd: C 43.31 H 5.11 N 8.38 Gd 23.65
