Note: Descriptions are shown in the official language in which they were submitted.
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Process for the Production of Cyclene
The invention relates to the subject that is characterized
in the claims, i.e., a new process for the production of cyclene.
Cyclene (1,4,7,10-tetraazacyclododecane) is a frequently
used starting material in the production of macrocyclic
complexing agents and is mainly used in the area of nuclear
resonance tomography as a ligand for.gadolinium. Two
preparations are already commercially available with ProHance(R)
of Bristol-Myers-Squibb and Dotarem(R) of Guerbet. Special
research and development projects also use cyclene as a starting
material. There is therefore a need for an easy and economical
process for the production of this educt.
One of the first published processes (Richman and Atkins, J.
Am. Chem. Soc. 1974, 96, p. 2268) employs the cyclization of a
sodium bis-sulfonamide with a corresponding functionalized
diethylene sulfonamide. In their synthesis, Weisman and Reed (J.
Org. Chem. 1996, 61, pp. 5186-5187) use the reaction of a bis-
thioimidoester with triethylenetetramine for the creation of a
tricyclic bis-imine, which is ultimately hydrolyzed to cyclene
after reduction.
The processes of V. Panetta et al. (Tetrahedron Lett. 1992,
Vol. 33, No. 38, pp. 5505-5508), which perform a cyclization of a
tetra-trifluoromethanesulfonic acid amide of triethylenetetramine
with 1,2-dibromoethane, follow a more indirect approach to
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cyclene. The last reaction step comprises the release of
cyclene. The process of the Nycomed Company (WO 96/28433) after
the production of tribenzylcyclene is also dependent on such a
procedure. The synthesis is accomplished by the reaction of a
suitable triamine with a monoamine or the two suitable diamines.
The process that is disclosed in DE 19608307 and that contains a
tetramerization of N-benzylaziridine as a key step also results
in tetrabenzylcyclene.
As described in WO 97/31005 and US 5,587,451, the Dow
Chemical Company uses a bis-imidazoline that starts from
triethylenetetramine as an intermediate product. The rings in
the tetracyclic intermediate product are closed with 1,2-
dibromoethane. The subsequent hydrolysis releases the cyclene.
As described in WO 97/49691, the Bracco Company uses a
direct approach to cyclene, which starts with the condensation of
triethylenetetramine with glyoxal -- which was already disclosed
by Weisman et al. (Tetrahedron Lett. 1980, Vol. 21, pp. 335-338).
Then, the latter is converted into a tetracyclic intermediate
compound by reaction with 1,2-dibromoethane. The removal of the
ethylene bridge that connects the four heteroatoms is carried out
by oxidation with bromine with subsequent hydrolysis (or else by
hydrolysis with a primary diamine, WO 98/49151). The total yield
is indicated with 25%.
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H H 1) Ca(OH)2 / H20 F7 BrCH2CH2Br
' n' 2) Glyoxal Na2C03 / DMAC N N
C 3h 75% ENXN 80 C 6h 45% CNXN
NHZ NH2 N N L-/
H H
Br2 / H20 + 2Br NaOH / H20 n
H H
pH 4.5 N pH 14 N N
25 C 18h CN
N!'185*C N15 bar EN N
~ + 5h 68% H' U 'H
Diagram 1: Synthesis Sequence of the Bracco Company (WO
97/49691)
The synthesis that is disclosed in WO 96/28432 of the
Nycomed Company resembles the above-described synthesis, with the
decisive difference being the hydrolysis of the central ethylene
bridge. Here, the reaction is achieved by addition of
hydroxylamine in an ethanolic solution while being heated. The
total yield for this reaction sequence is approximately 45%.
BrCH2CH2Br / 17
H __ H Glyoxal/
'N N' EtOH N N DMF N,,~ N
NHZ NH2 E ~ 20 C 20h 75% CN ~ N ~ 20 C 20h 70% o N" ND
1 r
H H ~_J
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NH2OH' HCI H\ n ~H
EtOH IN N N~
90 C 18h N
H~ U 'H
Diagram 2: Synthesis Sequence of the Nycomed Company (WO
96/28432)
Evaluation of the Process:
The process according to WO 97/49691, supported by
experimental reworking, has some decisive drawbacks, which are
summarized briefly below:
The production of the tricyclic compound cannot be
reproduced as described, since:
-- The calcium hydroxide cannot be quantitatively separated.
-- Larger amounts of water must be distilled off.
-- The product does not accumulate as an oil, as indicated.
The purification of the tetracyclic compound is very
expensive:
-- The extraction of the product from a solid reduces the
yield.
Hydrolysis into cyclene has proven to be very difficult:
-- An autoclave reaction must be performed at pH = 14 and at
185 C.
-- The product crystallizes poorly and with heavy
contamination from the reaction solution.
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The process according to WO 96/28432 also gives rise to
criticism. The basic drawbacks are listed below:
-- All synthesis stages have long stirring times.
-- The purification of the tetracyclic compound is carried
out via a preparative column chromatography.
-- The hydrolysis to cyclene lasts for a very long time,
and the indicated purification method does not yield
the product in the desired purity.
All other processes comprise multistage synthesis sequences,
in which intermediate products are isolated, which generally is
time-consuming and raw material-intensive. The process of
Weismann and Reed is ruled out for commercial synthesis, since it
is dependent on dithiooxamide (about DM 400/100 g) as one of the
starting materials. In the process of Richman and Atkins as well
as V. Panetta et al., correspondingly protected amines must first
be prepared. After the reaction has been completed, as also in
the process of the Dow Chemical Company, Nycomed (WO 96/28433)
and Schering (DE19608307), the cleavage of these protective
groups is necessary as an additional reaction step, which
produces a poorer material balance relative to the desired
product. In the case of tetramerization of benzylaziridine, it
is necessary to work with large amounts of carcinogenic
substances.
A profitable process should use raw materials that are as
reasonably priced, as environmentally safe and as easily
accessible as possible. The reaction times should also be short
and should occur with little energy use. Moreover, the amounts
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of material during the overall synthesis should be as small as
possible.
This object is achieved by this invention.
It has been found that a process for the production of
cyclene
H H
N N-
N N
H H
characterized in that in a single-pot process,
triethylenetetramine is reacted with 40% glyoxal at 20 C to 80 C
in a polar, protic solvent, preferably methanol, ethanol,
isopropanol, butanol, glycol, water or mixtures thereof,
especially preferably ethanol, within 4 to 40 hours, preferably
15 to 20 hours; after the solvent has been removed, the
intermediate tricyclic compound that is thus formed is alkylated
to the two secondary amine-nitrogens with a 1,2-difuntionalized
alkylating agent X(CHz)2X, in which X stands for a nucleofuge
group, preferably with 1,2-dibromoethane, 1,2-dichloroethane,
1,2-ditosylethane, 1,2-dimesylethane or 1,2-diiodoethane,
especially preferably with 1,2-dichloroethane in a polar aprotic
solvent, preferably in N,N-dimethylformamide (DMF), N,N-
dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), tetramethyl
urea, formamide or dimethylpropylene urea (DMPU), especially
preferably in DMF, optionally in the presence of an auxiliary
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base, preferably sodium carbonate, potassium carbonate, calcium
carbonate, sodium bicarbonate, potassium hydrogen carbonate,
magnesium carbonate, magnesium hydrogen carbonate, lithium
hydroxide or lithium carbonate, especially preferably without an
auxiliary base, at 20 to 120 C, preferably 30 to 70 C, within 2
to 24 hours, preferably 6 to 10 hours; after the solvent has been
removed, the thus obtained condensation product is treated with
hydrazine hydrate in a polar protic solvent, preferably methanol,
ethanol, isopropanol, butanol, glycol, water and/or mixtures
thereof, especially preferably ethanol, at a pH of 3 to 6,
preferably 3 to 4, 12 to 48 hours, preferably 25 to 35 hours, at
reflux temperature; then the cyclene is released from the cyclene
salt by adding a base, preferably sodium hydroxide, potassium
hydroxide, calcium hydroxide or a basic ion exchanger, especially
preferably sodium hydroxide and potassium hydroxide, and after
the reaction solution is evaporated to the dry state, it is
isolated,
surprisingly enough achieves the above-mentioned object.
The isolation of the cyclene is preferably carried out by
crystallization from toluene, trifluoromethylbenzene or
diethoxymethane, whereby the latter is especially preferred.
By way of example, diagram 3 again sheds light on the
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process of the synthesis according to the invention:
1) Giyoxal /EtOH
20 C 20h
H H 2) CICHZCH2C1 /DMF H H
40 C 8h
N N__ N N
3) HzN-NH2' H20 ~
NHZ NHZ pH 4/ HCI N N
TETA Reflux 30h H ~-- ~ H
4) KOH
pH13
5) DEM
50 - 65% von TETA
[Key:]
von = of
Advantages of the Process:
The process for the production of cyclene according to the
invention has considerable advantages relative to the previous
processes due to its design as a single-pot process.
-- No time-intensive and raw material-intensive isolating
steps of the intermediate products are necessary.
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-- The reaction with amine is carried out without
generating considerable amounts of by-products.
-- The raw materials are reasonably priced and easily
accessible.
-- Few wastes accumulate.
-- The total synthesis time is short.
-- A new, economical purification process for cyclene is
used.
-- The yield is higher than in the process of the prior
art.
The following example is used for a more detailed
explanation of the subject of the invention.
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Example 1
1,4,7,10 Tetraazacyclododecane (= cyclene):
50 g of triethylenetetramine (0.342 mol) is dissolved in 1 1
of ethanol and mixed with 39 ml of 40% glyoxal in water (0.342
mol) at room temperature. After 20 hours of stirring, the
solvent is distilled off in a vacuum, and an orange-colored oil,
which is taken up in 400 ml of dimethylformamide and mixed with
81.2 ml (101.5 g = 1.026 mol) of 1,2-dichloroethane, is obtained.
After 8 hours of stirring at 40 C, it is concentrated by
evaporation in a vacuum, the residue is taken up in 400 ml of
ethanol and acidified to about pH = 3-4 with 37% aqueous
hydrochloric acid. 166 ml (171 g = 3.42 mol) of hydrazine
hydrate is added to this reaction solution at room temperature,
and it is heated under reflux for 30 hours. The reaction
solution is set at pH = 13 with solid potassium hydroxide. The
reaction solution is subsequently concentrated by evaporation in
a vacuum, taken up once more in 100 ml of ethanol, and the
solvent is removed. The residue is mixed with 25 g of activated
carbon and 100 ml of formaldehyde diethylacetal, and it is heated
under reflux for some time before the hot solution is filtered
through a membrane. After the solution is cooled, the product is
isolated by filtration. 38.3 g of cyclene (0.222 mol = 65% of
theory) is obtained as a crystalline solid.
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Example 2
1,4,7,10-Tetraazacyclododecane (= cyclene)
50 g of triethylenetetramine (0.342 mol) is dissolved in 1 1
of ethanol and mixed at room temperature with 39 ml of 40%
glyoxal in water (0.342 mol). After 20 hours of stirring, the
solvent is distilled off in a vacuum, and an orange-colored oil
is obtained, which then is taken up in 400 ml of
dimethylformamide and mixed with 88.5 ml (192.8 g = 1.026 mol) of
1,2-dibromoethane. After 6 hours of stirring at 40 C, it is
concentrated by evaporation in a vacuum, the residue is taken up
in 400 ml of ethanol and acidified to pH = 3-4 with 37% aqueous
hydrochloric acid. 166 ml (171 g = 3.42 mol) of hydrazine
hydrate is added to this reaction solution at room temperature,
and it is heated under reflux for 30 hours. The reaction
solution is set at pH = 13 with solid potassium hydroxide. The
reaction solution is subsequently concentrated by evaporation in
a vacuum, taken up once more in 100 ml of ethanol, and the
solvent is removed again in a vacuum. The residue is mixed with
25 g of activated carbon and 150 ml of formaldehyde
diethylacetal, and it is heated under reflux for some time before
the hot solution is filtered through a membrane. After the
solution is cooled, the product is isolated by filtration.
39.5 g of cyclene (67% of theory) is obtained as a crystalline
solid.
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Example 3
1,4,7,10-Tetraazacyclododecane (= cyclene)
50 g of triethylenetetramine (0.342 mol) is dissolved in 1 1
of ethanol and mixed at room temperature with 39 ml of 40%
glyoxal in water (0.342 mol). After 20 hours of stirring, the
solvent is distilled off in a vacuum, and an orange-colored oil
is obtained, which is then taken up in 400 ml of
dimethylformamide and is mixed with 82.6 ml (274.8 g = 1.026 mol)
of 1,2-diiodoethane. After 5 hours of stirring at 40 C, it is
concentrated by evaporation in a vacuum, the residue is taken up
in 400 ml of ethanol and acidified to pH = 3-4 with 37% aqueous
hydrochloric acid. 166 ml (171 g = 3.42 mol) of hydrazine
hydrate is added to this reaction solution at room temperature,
and it is heated under reflux for 30 hours. The reaction
solution is set at pH = 13 with solid potassium hydroxide. The
reaction solution is subsequently concentrated by evaporation in
a vacuum, taken up once more in 100 ml of ethanol, and the
solvent is removed again in a vacuum. The residue is mixed with
25 g of activated carbon and 150 ml of formaldehyde
diethylacetal, and it is heated under reflux for some time before
the hot solution is filtered through a membrane. After the
solution is cooled, the product is isolated by filtration.
37.1 g of cyclene (63% of theory) is obtained as a crystalline
solid.
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Example 4
1,4,7,10-Tetraazacyclododecane (= cyclene)
50 g of triethylenetetramine (0.342 mol) is dissolved in i
ml of methanol and mixed at room temperature with 39 ml of 40%
glyoxal in water (0.342 mol). After 20 hours of stirring, the
solvent is distilled off in a vacuum, and an orange-colored oil
is obtained, which then is taken up in 400 ml of
dimethylformamide and mixed with 81.2 ml (101.5 g = 1.026 mol) of
1,2-dichloroethane. After 8 hours of stirring at 40 C, it is
concentrated by evaporation in a vacuum, the residue is taken up
in 400 ml of ethanol and acidified to pH = 3-4 with 37% aqueous
hydrochloric acid. 166 ml (171 g = 3.42 mol) of hydrazine
hydrate is added to this reaction solution at room temperature,
and it is heated under reflux for 30 hours. The reaction
solution is set at pH = 13 with solid potassium hydroxide. The
reaction solution is subsequently concentrated by evaporation in
a vacuum, taken up once more in 100 ml of ethanol, and the
solvent is removed again in a vacuum. The residue is mixed with
25 g of activated carbon and 150 ml of formaldehyde
diethylacetal, and it is heated under reflux for some time before
the hot solution is filtered through a membrane. After the
solution is cooled, the product is isolated by filtration.
37.7 g of cyclene (64% of theory) is obtained as a crystalline
solid.
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Example 5
1,4,7,10-Tetraazacyclododecane (= cyclene)
50 g of triethylenetetramine (0.342 mol) is dissolved in 1 1
of ethanol and mixed at room temperature with 39 ml of 40%
glyoxal in water (0.342 mol). After 20 hours of stirring, the
solvent is distilled off in a vacuum, and an orange-colored oil
is obtained, which then is taken up in 400 ml of dimethyl
acetamide and is mixed with 81.2 ml (101.5 g= 1.026 mol) of 1,2-
dichloroethane. After 8 hours of stirring at 40 C, it is
concentrated by evaporation in a vacuum, the residue is taken up
in 400 ml of ethanol and acidified to pH = 3-4 with 37% aqueous
hydrochloric acid. 166 ml (171 g = 3.42 mol) of hydrazine
hydrate is added to this reaction solution at room temperature
and heated under reflux for 30 hours. The reaction solution is
set at pH = 13 with solid potassium hydroxide. The reaction
solution is subsequently concentrated by evaporation in a vacuum,
taken up once more in 100 ml of ethanol, and the solvent is
removed again in a vacuum. The residue is mixed with 25 g of
activated carbon and 150 ml of formaldehyde diethylacetal and
heated under reflux for some time before the hot solution is
filtered through a membrane. After the solution is cooled, the
product is isolated by filtration. 37.7 g of cyclene (64% of
theory) is obtained as a crystalline solid.
CA 02353680 2001-05-30
Example 6
1,4,7,10-Tetraazacyclododecane (= cyclene)
50 g of triethylenetetramine (0.342 mol) is dissolved in 1 1
of ethanol and mixed at room temperature with 39 ml of 40%
glyoxal in water (0.342 mol). After 20 hours of stirring, the
solvent is distilled off in a vacuum, and an orange-colored oil
is obtained, which then is taken up in 400 ml of tetramethylurea
and mixed with 81.2 ml (101.5 g = 1.026 mol) of 1,2-
dichloroethane. After 8 hours of stirring at 40 C, it is
concentrated by evaporation in a vacuum, the residue is taken up
in 400 ml of ethanol and acidified to pH = 3-4 with 37% aqueous
hydrochloric acid. 166 ml (171 g = 3.42 mol) of hydrazine
hydrate is added to this reaction solution at room temperature
and heated under reflux for 30 hours. The reaction solution is
set at pH = 13 with solid potassium hydroxide. The reaction
solution is subsequently concentrated by evaporation in a vacuum,
taken up once more in 100 ml of ethanol, and the solvent is.again
removed in a vacuum. The residue is mixed with 25 g of activated
carbon and 150 ml of formaldehyde diethylacetal, and it is heated
under reflux for some time before the hot solution is filtered
through a membrane. After the solution is cooled, the product is
isolated by filtration. 37.1 g of cyclene (63% of theory) is
obtained as a crystalline solid.
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Example 7
1,4,7,10-Tetraazacyclododecane (= cyclene)
50 g of triethylenetetramine (0.342 mol) is dissolved in 1 1
of ethanol and mixed at room temperature with 39 ml of 40%
glyoxal in water (0.342 mol). After 20 hours of stirring, the
solvent is distilled off in a vacuum, and an orange-colored oil
is obtained, which then is taken up in 400 ml of tetramethylurea
and mixed with 88.5 ml (192.8 g = 1.026 mol) of 1,2-
dibromoethane. After 6 hours of stirring at 40 C, it is
concentrated by evaporation in a vacuum, the residue is taken up
in 400 ml of ethanol and acidified to pH = 3-4 with 37% aqueous
hydrochloric acid. 166 ml (171 g = 3.42 mol) of hydrazine
hydrate is added to this reaction solution at room temperature
and heated under reflux for 30 hours. The reaction solution is
set at pH = 13 with solid potassium hydroxide. The reaction
solution is subsequently concentrated by evaporation in a vacuum,
taken up once more in 100 ml of ethanol, and the solvent is
removed again in a vacuum. The residue is mixed with 25 g of
activated carbon and 150 ml of formaldehyde diethylacetal and
heated under reflux for some time before the hot solution is
filtered through a membrane. After the solution is cooled, the
product is isolated by filtration. 37.6 g of cyclene (64%
measured) is obtained as a crystalline solid.
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Example 8
1,4,7,10-Tetraazacyclododecane (= cyclene)
50 g of triethylenetetramine (0.342 mol) is dissolved in 1 1
of methanol and mixed at room temperature with 39 ml of 40%
glyoxal in water (0.342 mol). After 20 hours of stirring, the
solvent is distilled off in a vacuum, and an orange-colored oil
is obtained, which then is taken up in 400 ml of
dimethylformamide and mixed with 88.5 ml (192.8 g = 1.026 mol) of
1,2-dibromoethane. After 6 hours of stirring at 40 C, it is
concentrated by evaporation in a vacuum, the residue is taken up
in 400 ml of ethanol and acidified to pH = 3-4 with 37% aqueous
hydrochloric acid. 166 ml (171 g = 3.42 mol) of hydrazine
hydrate is added to this reaction solution and heated under
reflux for 30 hours. The reaction solution is set at pH = 13
with solid potassium hydroxide. The reaction solution is
subsequently concentrated by evaporation in a vacuum, taken up
once more in 100 ml of ethanol, and the solvent is removed again
in a vacuum. The residue is mixed with 25 g of activated carbon
and 150 ml of formaldehyde diethylacetal and heated under reflux
for some time before the hot solution is filtered through a
membrane. After the solution is cooled, the product is isolated
by filtration. 35.9 g of cyclene (61% of theory) is obtained as
a crystalline solid.
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Example 9
1,4,7,10-Tetraazacyclododecane (= cyclene)
50 g of triethylenetetramine (0.342 mol) is dissolved in 1 1
of ethanol and mixed at room temperature with 39 ml of 40%
glyoxal in water (0.342 mol). After 20 hours of stirring, the
solvent is distilled off in a vacuum, and an orange-colored oil
is obtained, which then is taken up in 400 ml of
dimethylformamide and mixed with 81.2 ml (101.5 g = 1.026 mol) of
1,2-dichloroethane. After 8 hours of stirring at 40 C, it is
concentrated by evaporation in a vacuum, the residue is taken up
in 400 ml of ethanol and acidified to pH = 3-4 with 37% aqueous
hydrochloric acid. 166 ml (171 g = 3.42 mol) of hydrazine
hydrate is added at room temperature to this reaction solution,
and then it is heated under reflux for 30 hours. The reaction
solution is set at pH = 13 with solid potassium hydroxide. The
reaction solution is subsequently concentrated by evaporation in
a vacuum, taken up once more in 100 ml of ethanol, and the
solvent is removed again in a vacuum. The residue is mixed with
25 g of activated carbon and 200 ml of toluene and heated under
reflux for some time before the hot solution is filtered through
a membrane. After the solution is cooled, the product is
isolated by filtration. 35.8 g of cyclene (61% of theory) is
obtained as a crystalline solid.
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Example 10
1,4,7,10-Tetraazacyclododecane (= cyclene)
50 g of triethylenetetramine (0.342 mol) is dissolved in 1 1
of 2-propanol and mixed at room temperature with 39 ml of 40%
glyoxal in water (0.342 mol). After 20 hours of stirring, the
solvent is distilled off in a vacuum, and an orange-colored oil
is obtained, which then is taken up in 400 ml of
dimethylformamide and mixed with 81.2 ml (101.5 g = 1.026 mol) of
1,2-dichloroethane. After 8 hours of stirring at 40 C, it is
concentrated by evaporation in a vacuum, the residue is taken up
in 400 ml of ethanol and acidified to pH = 3-4 with 37% aqueous
hydrochloric acid. 166 ml (171 g = 3.42 mol) of hydrazine
hydrate is added to this reaction solution at room temperature
and heated under reflux for 30 hours. The reaction solution is
set at pH = 13 with solid potassium hydroxide. The reaction
solution is subsequently concentrated by evaporation in a vacuum,
taken up once more in 100 ml of ethanol, and the solvent is
removed again in a vacuum. The residue is mixed with 25 g of
activated carbon and 150 ml of formaldehyde diethylacetal and
heated under reflux for some time before the hot solution is
filtered through a membrane. After the solution is cooled, the
product is isolated by filtration. 37.2 g of cyclene (63% of
theory) is obtained as a crystalline solid.
