A method for the preparation of cyclen

Abstract

The present invention discloses a method for the preparation of cyclen (1,4,7,10-tetraazacyclododecane) including one or more of the following steps: • (1) intermediate 1 is reacted with butanedione in the presence of an ether solvent to form intermediate 2, • (2) Intermediate 2 is reacted with glyoxal in the presence of a solvent, a reducing agent and benzotriazole to form intermediate 3.

Description

[0001] TITLE

[0002] A method for the preparation of cyclen

[0003] TECHNICAL FIELD

[0004] The present invention relates to the field of organic synthesis, specifically, to a method for the preparation of cyclen.

[0005] BACKGROUND OF THE INVENTION

[0006] Cyclen (also known as 1,4,7,10-tetraazacyclododecane) is a very important intermediate for synthesizing therapeutic drugs for diagnostic kits. Cyclen can be used to remove stones in the human body, inhibit the loss caused by myocardial ischemia reperfusion, especially in the manufacture of magnetic resonance imaging (MRI), radiological CT, ultrasound imaging and other medical imaging technology contrast agent, as well as malignant tumors of radiotherapy drugs.

[0007] Cyclen and its derivatives are precursors of macrocyclic chelating agents for metal ions because they can form very stable complexes with ions, especially with paramagnetic metal ions such as gadolinium ions. Such complexes are used in medical diagnostic field because they do not exhibit a high toxicity caused by free ions, so it is very safe.

[0008] Currently, the main synthetic methods of macrocycles are Stetter synthesis, Richman-Atkins synthesis, Weisman synthesis, diethyl oxalate condensation (Wei Junfa et al., Wuhan University, 1997), glyoxal condensation (Berlacol International AG) and amide condensation (reported by Zhang Juan et al. from the Department of Chemical Engineering, Northwestern Polytechnical University, 2005 and Liu Yan from East China Normal University, 2012, and others). Among them, the Stetter synthesis is a pioneering method for the synthesis of macrocycles, but it is not easy to obtain the raw materials and must be carried out under highly diluted conditions, so it is less used nowadays. The improved Richman-Atkins method is the classic synthesis method of cyclen, but this method has many steps, high reagent consumption, high requirements for operators, and is difficult to realize in industrial production. The Weisman method uses dithiocarbamide to form a salt that is reacted with triethylenetetramine (TETA) and then hydrolyzed to get the target product. Although this method is only a three-step reaction, the raw material dithiocarbamide is expensive, which is also unfavorable for industrial production. The diethyl oxalate condensation method has a low overall yield. The process reported in Tetrahedron Letters, 39 (1998), 6861-6864 includes the use of 1,2-dibromoethane, which is time-consuming and the intermediates need to be purified by passing through a column, which is also not suitable for industrialization. J. Org. Chem.

[0009] 2002, 67, 4081-4085 reports a reaction between triethylenetetramine (TETA) and N,N- dimethylformamide dimethyl acetal and then with 1,2-dibromoethane to form a quaternary ammonium salt which is then hydrolyzed under harsh alkaline conditions to form cyclen. The intermediate quaternary ammonium salt of this synthetic route is difficult to detect and the progress of the reaction cannot be tracked in real time, which is also unfavorable for an industrial production. Therefore, it is desirable to develop a method for the synthesis of cyclen with low cost and high efficiency.

[0010] CONTENT OF THE INVENTION

[0011] The technical problem to be solved by the present invention is to provide an improved method for the preparation of cyclen to overcome the drawbacks of the preparation methods in the prior art. The preparation method of the present invention is simple in operation, high in capacity, simple in equipment, safe, low in cost and suitable for industrialized production. The present invention provides a method for the preparation of intermediate 2 comprising a step of reacting intermediate 1 with butanedione in the presence of an ether solvent:

[0012]

[0013] Intermediate 2.

[0014] In one embodiment, said ether solvent is tetrahydrofuran.

[0015] In one embodiment, the molar ratio of intermediate 1 to butanedione is 1: 1.0-2.0, preferably 1:(1.0-1.1); further preferably 1:1.

[0016] In one embodiment, the mass volume ratio of intermediate 1 to solvent is 0.06-1.0 g / mL, preferably 0.08 g / mL.

[0017] In one embodiment, the reaction has a reaction time of 1-1 Oh; preferably 1-4h; further preferably 2h.

[0018] In one embodiment, the reaction proceeds directly to the next step without separating the reaction solution.

[0019] In one embodiment, the reaction is operated by dropwise addition of a mixture of butanedione and solvent to a mixture of intermediate 1 and solvent at -15°C to 10°C and keeping this temperature for 2h. In one embodiment, the reaction is carried out in the presence of nitrogen.

[0020] The present invention also provides a method for the preparation of intermediate 3 comprising an additional step 2 of reacting intermediate 2 with glyoxal in the presence of a solvent, a reducing agent and benzotriazole:

[0021]

[0022] The present invention also provides a method of preparing intermediate 3 comprising the steps of

[0023] (1) Reacting intermediate 1 and butanedione in the presence of a solvent to obtain intermediate 2:

[0024]

[0025] Intermediate 2,

[0026] (2) Reacting intermediate 2 and glyoxal in the presence of a solvent, a reducing agent and benzotriazole to obtain intermediate 3:

[0027]

[0028] In one embodiment, steps (1) and (2) are carried out in the same solvent, preferably in tetrahydrofuran (THF).

[0029] In one embodiment, the reducing agent in step (2) is selected from lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, calcium borohydride and sodium triacetoxyborohydride, preferably sodium borohydride.

[0030] In one embodiment, a 40% aqueous solution of glyoxal is used in step (2).

[0031] In one embodiment, the molar ratio of intermediate 1 in step (1) to benzotriazole in step (2) is 1:(1.8-2.5), preferably 1:(2.1-2.3), most preferably 1:2.3.

[0032] In one embodiment, the mass to volume ratio of intermediate 1 in step (1) to the solvent in step (2) is 0.25-0.40 g / mL, preferably 0.33 g / mL.

[0033] In one embodiment, the molar ratio of intermediate 1 in step (1) to the reducing agent in step (2) is 1:(1.5-2.0), preferably 1:(1.7-1.9); further preferably 1:1.8.

[0034] In one embodiment, the molar ratio of intermediate 1 in step (1) to glyoxal in step (2) is 1.0:(1.0-2.0), preferably 1.0 :(1.0-1.1), further preferably 1.0:1.0.

[0035] In one embodiment, the reaction temperature in reaction step (2) ranges from -20°C to 0°C; preferably from -15°C to -10°C or-10°C to 0°C.

[0036] In one embodiment, the reaction time of reaction step (2) is from 20-30 h, preferably 25 h. In one embodiment, the reaction step (2) further comprises a post- treatment step of quenching to pH 5 to 6 with hydrochloric acid (e.g., 36% hydrochloric acid), and concentrating the solvent. In one embodiment, the reaction operation of reaction step (2) is as follows:

[0037] - dropwise addition of a solution of benzotriazole and tetrahydrofuran to the reaction solution of step 1 at -15°C to -10°C,

[0038] - stirring the reaction mixture for 30 min at -15°C to -10°C,

[0039] - dropwise addition of a 40% aqueous solution of glyoxal at -15°C to -10°C, - a low temperature for 15h,

[0040] - adding NaBH4 at -10°C to 0°C,

[0041] hold the reaction for 10h.

[0042] The present invention also provides a method of preparing intermediate 4 comprising a step (3) of reacting intermediate 3 with hydrochloric acid in the presence of a solvent to obtain intermediate 4:

[0043]

[0044] Intermediate 3 Intermediate 4.

[0045] In one embodiment, the solvent in step (3) is an alcohol, a nitrile or an ether. The alcohol may be methanol or ethanol, preferably methanol. The nitrile is preferably acetonitrile. The ether preferably tetrahydrofuran.

[0046] In one embodiment, the hydrochloric acid in step (3) is 36% hydrochloric acid.

[0047] In one embodiment, the mass to volume ratio of intermediate 1 in step (1) to solvent in step (3) is 0.4-0.6 g / mL; preferably 0.5 g / mL.

[0048] In one embodiment, the molar ratio of intermediate 1 in step (1) to hydrochloric acid in step (3) is 1 :(8-12), preferably 1:10.

[0049] In one embodiment, the reaction in step 3 is operated as follows:

[0050] - adding solvent to the reactants of step (2),

[0051] - adding 36% hydrochloric acid dropwise at 40°C-60°C,

[0052] raising the temperature to 60°C-70°C,

[0053] - stirring the reaction mixture for 5h, and

[0054] lowering the temperature to 40°C-50°C for filtration to obtain intermediate 4.

[0055] In one embodiment, the reaction in step (3) further comprises a post-treatment step of recovering benzotriazole by means of filtering.

[0056] The present invention also provides a method of preparing intermediate 5 comprising a step

[0057]

[0058]

[0059] Intermediate 4 Intermediate 5.

[0060] In one embodiment, the solvent in step (4) is water.

[0061] In one embodiment, the base in said step (4) is sodium hydroxide, preferably a 48% aqueous solution of sodium hydroxide.

[0062] In one embodiment, the mass to volume ratio of intermediate 1 said step (1) to the solvent in step (4) is 0.25-0.4 g / mL, preferably 0.33 g / mL.

[0063] In one embodiment, the molar ratio of intermediate 1 in step (1) to the base in step (4) is 1 :(2.0-4.0), preferably 1:(2.5-3.5).

[0064] In one embodiment, the reaction in step (4) is operated as follows:

[0065] - the reaction product of step (3) is added to water,

[0066] - 48% aqueous sodium hydroxide solution is added dropwise to pH=14,

[0067] - the reaction mixture is cooled down to 0°C and filtered.

[0068] The present invention also provides a method of preparing cyclen comprising a step (5) of dehydrating intermediate 5 in a solvent to obtain cyclen:

[0069]

[0070] Intermediate 5 Cyclen (1 ,4,7,10-tetraazacyclododecane).

[0071] In one embodiment, the solvent in step 5 is a benzene solvent, preferably toluene.

[0072] In one embodiment, the mass to volume ratio of intermediate 1 in step (1) to the solvent in step (5) is 0.15-0.25 g / mL, preferably 0.2 g / mL. In one embodiment, the reaction in step (5) is operated as follows:

[0073] - the reaction product of step 4 is mixed with toluene,

[0074] - the reaction mixture is heated up to 100°C-150°C and water was separated under reflux,

[0075] - the reaction mixture is filtered at a temperature of 80°C-90°C,

[0076] - toluene is removed from the filtrate under reduced pressure,

[0077] - the reaction mixture is cooled down to 0°C to precipitate cyclen crystals,

[0078] - the cyclen crystals are filtered and dried.

[0079] The present invention also provides a method of refining crude triethylenetetramine comprising the following steps:

[0080] (i) Crude triethylenetetramine is dissolved in toluene and water and precipitated in the presence of triethylenetetramine hydrate crystals,

[0081] (ii) Separation of triethylenetetramine hydrate into water in the presence of toluene to yield triethylenetetramine (i.e. intermediate 1).

[0082] In one embodiment, the volume ratio of toluene to water in said refining step (i) is (12-14):1; preferably 13.3:1.

[0083] In one embodiment, the mass to volume ratio of crude triethylenetetramine to solvent in refining step (i) is 0.4-0.6 g / mL, preferably 0.5 g / mL.

[0084] In one embodiment, the molar ratio of crude triethylenetetramine to crystalline species of triethylenetetramine hydrate in refining step (i) is 1:(0.01-0.02), preferably 1:0.014.

[0085] In one embodiment, the reaction time of refining step (i) is 1 to 4h; preferably 2h.

[0086] In one embodiment, the temperature of refining step (i) is 30°C-50°C; preferably 35°C-45°C. In one embodiment, the refining method (i) further comprises the post-treatment steps of:

[0087] - cooling down the reaction mixture to 0°C,

[0088] - filtration to obtain solid triethylenetetramine.

[0089] In one embodiment, the mass to volume ratio of crude triethylenetetramine in the refining step (i) to toluene in refining step (ii) is 0.4-0.52 g / mL, preferably 0.49 g / mL.

[0090] In one embodiment, the temperature of refining step (ii) is 90°C-150°C; preferably 100°C-150°C.

[0091] The present invention also provides a method for the preparation of cyclen (1,4,7,10-tetraazacyclododecane) comprising one or more of the following steps: (1) reacting intermediate 1 with butanedione in the presence of an ether solvent to obtain intermediate 2:

[0092]

[0093] Intermediate 2,

[0094] (2) reacting intermediate 2 with glyoxal in the presence of a solvent, a reducing agent and benzotriazole to obtain intermediate 3:

[0095]

[0096] (3) reacting intermediate 3 with hydrochloric acid in the presence of a solvent and a base to obtain intermediate 4:

[0097]

[0098] Intermediate 3 Intermediate 4,

[0099] (4) reacting intermediate 4 by with a base in the presence of a solvent to obtain intermediate 5:

[0100]

[0101] Intermediate 4 Intermediate 5,

[0102] (5) dehydrating intermediate 5 in a solvent to obtain cyclen:

[0103]

[0104] Intermediate 5 Cyclen .

[0105] The reaction conditions of steps (1) to (5) are as described above.

[0106] The reagents and raw materials used in the present invention are commercially available. The present invention provides an improved method for the preparation of cyclen with the following advantages:

[0107] 1) The reaction raw materials are simple and easy to obtain with few reaction steps. 2) The reaction can be carried out under mild conditions and low equipment requirements.

[0108] 3) The production can easily be scaled up.

[0109] 4) Only small amounts of waste are generated, thus improving the protection of the environment. DESCRIPTION OF THE ACCOMPANYING FIGURES

[0110] FIG. 1 shows the purity profile of cyclen.

[0111] SPECIFIC EMBODIMENTS - EXAMPLES

[0112] The invention is further described below by way of embodiments but does not thereby limit the invention to the scope of the described embodiments.

[0113] The experimental methods in the following embodiments for which specific conditions are not indicated are selected in accordance with conventional methods and conditions or in accordance with the trade specification.

[0114] Example 1: Preparation of triethylenetetramine (TETA, Intermediate 1)

[0115] Crude triethylenetetramine (50.0 g, 342.1 mmol) was added to toluene (87.00 g, 99.8 ml) and water (7.50 g) was added dropwise. The solution was warmed up to 35°C-45°C and maintained at that temperature for 2h. After cooling down to 30°C-40°C seed crystals of triethylenetetramine (0.90 g, 4.9 mmol) were added.

[0116] Seed crystals of triethylenetetramine (TETA) can be obtained by adding Toluene (89.0 g, 102.1 ml) to triethylenetetramine hydrate, heat up to 100°C-150°C, slowly cooling down to 0°C and filtration. Triethylenetetramine is obtained with 71% yield and 99% purity.

[0117] Example 2: Preparation of Intermediate 2

[0118]

[0119] Intermediate 2

[0120] Triethylenetetramine (Intermediate 1) (30.0 g, 205.3 mmol) was added to tetrahydrofuran (106.4 g, 119.6 ml) under nitrogen atmosphere and cooled down to below -10°C under stirring. A mixture of butanedione (17.7 g, 205.3 mmol) in tetrahydrofuran (226.6 g, 254.6 ml) was added dropwise at -15°C to -10°C and the temperature was maintained for 2h. Intermediate 2 was thus obtained in solution with 88% yield and 91% purity. Example 3: Preparation of Intermediate 3

[0121]

[0122] Intermediate 2

[0123] Intermediate 3

[0124] Benzotriazole (56.2 g, 471.8 mmol) and tetrahydrofuran (79.88 g, 89.8 ml) were added dropwise to the reaction solution obtained in Example 2 at -15 to 10°C and stirred at low temperature for 30 min. 40% aqueous glyoxal (30.1 g, 207.6 mmol) was added dropwise and the reaction mixture was held at low temperature for additional 15h. NaBH4 (13.9 g, 367.4 mmol) was slowly added in batches at -10 to 0°C. The reaction was continued at -10 to 0°C for 10h and then quenched to pH 5-6 with 36% hydrochloric acid (52.0g). Intermediate 3 was obtained in solution with 78% yield and 87% purity.

[0125] Example 4: Preparation of Intermediate 4

[0126]

[0127] Intermediate 3 Intermediate 4

[0128] Methanol (47.4 g, 60 ml) was added to a concentrated solution of the reaction mixture and 36% hydrochloric acid (208.0 g, 2.05 mol) was added dropwise at 40°C~60°C. At the end of the addition, the reaction mixture was warmed up to 60°C-70°C and reacted for 5h. Intermediate 4 was obtained by filtration at a reduced temperature of 40°C-50°C, with a yield of 83% and a purity of 99.2%. Benzotriazole was recovered from the mother liquor.

[0129] Example 5: Preparation of Intermediate 5

[0130]

[0131] Intermediate 4 Intermediate 5

[0132] Intermediate 4 was added to water (90.0 g) followed by dropwise addition of 48% aqueous sodium hydroxide solution (53.8 g, 645.6 mmol) to pH 14, slowly cooled down to 0°C and then filtered to obtain Intermediate 5 with 94% yield and 100.0% purity.

[0133] Example 6: Preparation of cyclen (1,4,7,10-tetraazacyclododecane)

[0134]

[0135] Intermediate 5 Cyclen

[0136] Intermediate 5 was added to toluene (130.5 g, 150 ml) and the temperature was raised to 100-150°C. The water was separated under reflux. After the removal of the water, the reaction mixture was filtered at 80-90 °C and the filtrate was concentrated under reduced pressure from most of the toluene and then cooled down to 0°C. precipitation of crystals, filtering drying to obtain cyclen with 93% yield and 100.0% purity. The purity spectrum is shown in Figure 1. The overall yield from intermediate 1 to the cyclen was 50%. The purity spectrum is shown in Figure 1 , the data are shown in the following Table 1 :

[0137]

[0138] Instrumentation for analysis:

[0139] Gas chromatograph: Agilent; GC-7890A

[0140] Column: gas chromatography column

[0141]

[0142] Inlet temperature: 280°C,

[0143] Detector temperature: 300°C,

[0144] Inlet volume: 1 pL,

[0145] Split ratio: 20:1,

[0146] Column flow rate: 2.2 mL / min,

[0147] Carrier gas: H2 (or He),

[0148] Hydrogen flow rate: 40 mL / min,

[0149] Air flow rate: 400 mL / min,

[0150] Tail blow flow: 25 mL / min.

[0151] Gas phase external standard test operation procedure

[0152] 1. Solution preparation

[0153] Standard solution: weigh 40 mg of standard in 10 mL volumetric flask, add methanol to dissolve and dilute. Mix well.

[0154] Sample solution: Take the sample to be measured and put it into the injection bottle.

[0155] Blank solution: Methanol

[0156] 2. Measurement sequence

[0157] After the instrument is stabilized, 1 pL of blank solution, standard solution and sample solution is injected and the chromatogram is recorded.

[0158] >

[0159] <

[0160]

[0161] A = (Maximum value - Minimum value) / Average value * 100% 3. Calculation of results

[0162] The content of target substance is calculated according to the following formula:

[0163]

[0164] Eq:

[0165] ASPL - Peak area of the target in the sample solution.

[0166] ASTD - Average peak area of the target in the standard solution.

[0167] CSTD - Concentration of the target in the standard solution, mg / mL. p - Density of the solution to be tested.

[0168] Gas phase area normalization test procedure

[0169] 1. Solution preparation

[0170] Sample solution: weigh 300 mg of sample (accurate to 0.1 mg) in a 10 mL volumetric flask, dissolve with methanol and dilute to scale.

[0171] Dissolve with methanol and dilute to scale, mix well.

[0172] Blank solution: methanol

[0173] 2. Measurement sequence

[0174] After the instrument is stabilized, feed 1 pL into the blank solution and sample solution and record the chromatogram.

[0175] >

[0176]

[0177] 3. Calculation of results

[0178] Unknown single impurities and target products were calculated by the area normalization method. Peaks caused by the blank solution were not counted. Peaks less than 0.05% are not counted. When the product is a solution, the purity of the product is measured by the gas-phase area normalization method as described above.

[0179] When the product is a solid, it is first dissolved in a conventional solvent in the field and then the purity of the product is measured by the gas-phase area normalization method described above.

Claims

CLAIMS1. A method for the preparation of intermediate 2 comprising a step (1) of reacting intermediate 1 with butanedione in the presence of an ether solvent:Intermediate 2.

2. The method according to claim 1, characterized in that it satisfies one or more of the following conditions:(1) the ether solvent is tetrahydrofuran,(2) the molar ratio of intermediate 1 to butanedione is 1:(1.0-2.0), preferably 1 :(1.0- 1.1); further preferably 1:1,(3) the mass to volume ratio of intermediate 1 to solvent is 0.06-1.0 g / mL, preferably 0.08 g / mL,(4) the reaction is carried out in the presence of nitrogen.

3. The method according to claim 1 or claim 2 comprising an additional step (2) of reacting intermediate 2 with glyoxal in the presence of a solvent, a reducing agent and benzotriazole to obtain intermediate 3:Intermediate 2Intermediate 3.A method for the preparation of intermediate 3 comprising the steps of(1) Reacting intermediate 1 and butanedione in the presence of a solvent to obtain intermediate 2:Intermediate 2,(2) Reacting intermediate 2 and glyoxal in the presence of a solvent, a reducing agent and benzotriazole to obtain intermediate 3:

5. The method of preparing intermediate 3 according to claim 3 or claim 4, characterized in that it satisfies one or more of the following conditions:(1) the solvent in step (2) is tetrahydrofuran,(2) the solvent in step (2) is the same solvent as in step (1),(3) the reducing agent is lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, calcium borohydride or sodium triacetoxyborohydride, preferably sodium borohydride,(4) the glyoxal is a 40% aqueous solution of glyoxal,(5) The molar ratio of intermediate 1 to benzotriazole is 1 :(1.8-2.5), preferably 1 :(2.1- 2.3),(6) The mass to volume ratio of intermediate 1 to the solvent in step (2) is 0.25-0.40 g / mL, preferably 0.33 g / mL,(7) The molar ratio of intermediate 1 to reducing agent is 1:(1.5-2.0), preferably 1 :(1.7- 1.9),(8) The molar ratio of intermediate 1 to glyoxal is 1:(1.0-2.0), 1: preferably 1:(1.0-1.1).

6. The method according to one of claims 3-5 comprising an additional step (3) of reacting intermediate 3 and hydrochloric acid in the presence of a solvent to obtain intermediate 4:Intermediate 3 Intermediate 4.

7. The method according to claim 6, characterized in that it satisfies one or more of the following conditions:(1) the solvent in step (3) is an alcohol solvent, preferably methanol or ethanol; a nitrile solvent, preferably acetonitrile; or an ether solvent, preferably tetrahydrofuran, (2) the hydrochloric acid is 36% hydrochloric acid,(3) the mass to volume ratio of intermediate 1 to solvent of step (3) is 0.4-0.6 g / mL, preferably 0.5 g / mL,(4) the molar ratio of said intermediate 1 in step (1) to hydrochloric acid is 1 :(8-12), preferably 1:10.

8. The method according to claim 6 or claim 7 comprising an additional step (4) of reacting intermediate 4 in the presence of a solvent and a base to obtain intermediate 5:Intermediate 4 Intermediate 5.

9. The method of claim 8, characterized in that it satisfies one or more of the following conditions:(1) the solvent in step (4) is water,(2) the base in step (4) is sodium hydroxide; preferably a 48% aqueous sodium hydroxide solution,(3) The mass to volume ratio of intermediate 1 to solvent in step (4) is 0.25-0.4 g / mL, preferably 0.33 g / mL,(4) The molar ratio of said intermediate 1 to base in step (4) is 4 is 1 :(2-4), preferably 1:(2.5-3.5).

10. The method according to claim 8 or claim 9 comprising an additional step (5) of dehydrating intermediate 5 in a solvent:Intermediate 5 Cyclen (1 ,4,7,10-tetraazacyclododecane).

11. The method of claim 10, characterized in that it satisfies one or more of the following conditions:(1) the solvent in step (5) is a benzene solvent, preferably toluene,(2) the mass to volume ratio of intermediate 1 to solvent in step 5 is 0.15-0.25 g / mL, preferably 0.2 g / mL.

12. A method according to any of the claims comprising an initial step of refining crude triethylenetetramine (intermediate 1) comprising the following steps:(i) crude triethylenetetramine is dissolved in toluene and water and precipitated in the presence of seed crystals of triethylenetetramine hydrate,(ii) hydrate water is separated from triethylenetetramine in the presence of toluene to obtain dry triethylenetetramine.

13. Use of one or more of the methods according to any of the preceding claims for the preparation of cyclen (1,4,7,10-tetraazacyclododecane).

14. A process for the preparation of cyclen (1,4,7,10-tetraazacyclododecane) comprising one or more methods according to any of the preceding claims 1 to 12.

15. A process for the preparation of cyclen (1,4,7,10-tetraazacyclododecane) comprising the steps of(1) Reacting intermediate 1 and butanedione in the presence of a solvent to obtain intermediate 2:Intermediate 2,(2) Reacting intermediate 2 and glyoxal in the presence of a solvent, a reducing agent and benzotriazole to obtain intermediate 3:Intermediate 2Intermediate 3.

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