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Chemical Structure| 294-90-6 Chemical Structure| 294-90-6
Chemical Structure| 294-90-6

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Cyclen compounds are capable of selectively binding cations and used as a ligand in chemistry for instance with chemicals used in MRI contrast agents.

4.5 *For Research Use Only! Not for Human Use. We Do Not Sell to Patients.

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Tang, Jian-Hong ; Luo, Minrui ; Tsao, Wilhelmina ; Waters, Emily Alexandria ; Parigi, Giacomo ; Luchinat, Claudio , et al.

Abstract: Glycoconjugates forming from the conjugation of carbohydrates to other biomolecules, such as proteins, lipids, or other carbohydrates, are essential components of mammalian cells and are involved in numerous biological processes. Due to the capability of sugars to form multiple hydrogen bonds, many synthetic glycoconjugates are desirable biocompatible platforms for imaging, diagnostics, drugs, and supramolecular self-assemblies. Herein, we present a multimeric galactose functionalized paramagnetic gadolinium (Gd(III)) chelate that displays spontaneous dynamic aggregation in aqueous conditions. The dynamic aggregation of the Gd(III) complex was shown by the concentration-dependent magnetic resonance (MR) relaxation measurements, nuclear magnetic resonance dispersion (NMRD) analysis, and dynamic light scattering (DLS). Notably, these data showed a nonlinear relationship between magnetic resonance relaxation rate and concentrations (0.03−1.35 mM), and a large DLS hydrodynamic radius was observed in the high-concentration solutions. MR phantom images were acquired to visualize real-time dynamic aggregation behaviors in aqueous solutions. The in situ visualization of the dynamic self-assembling process of multivalent glycoconjugates has rarely been reported.

Purchased from AmBeed: ; ; 294-90-6

Li, Bowen ; Manan, Rajith Singh ; Liang, Shun-Qing ; Gordon, Akiva ; Jiang, Allen ; Varley, Andrew , et al.

Abstract: The expanding applications of nonviral genomic medicines in the lung remain restricted by delivery challenges. Here, leveraging a high-throughput platform, we synthesize and screen a combinatorial library of biodegradable ionizable lipids to build inhalable delivery vehicles for mRNA and CRISPR-Cas9 gene editors. Lead lipid nanoparticles are amenable for repeated intratracheal dosing and could achieve efficient gene editing in lung epithelium, providing avenues for gene therapy of congenital lung diseases.

Alternative Products

Product Details of Cyclen

CAS No. :294-90-6
Formula : C8H20N4
M.W : 172.27
SMILES Code : C1CNCCNCCNCCN1
English Name :1,4,7,10-Tetraazacyclododecane
MDL No. :MFCD00066281
InChI Key :QBPPRVHXOZRESW-UHFFFAOYSA-N
Pubchem ID :64963

Safety of Cyclen

Application In Synthesis of Cyclen

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 294-90-6 ]

[ 294-90-6 ] Synthesis Path-Downstream   1~74

  • 1
  • [ 10045-25-7 ]
  • [ 294-90-6 ]
YieldReaction ConditionsOperation in experiment
95% With hydrogenchloride 1-10 1,4,7-tetraazacyclododecane Dowex TM 1 × 8 200-400 mesh strong basic type I anion exchange resin (Cl type) was placed in a 300 mL beaker and dissolved in 1 M HCl.After filtering this with Nutche, the obtained filtrate was dissolved in distilled water and poured into a chromatographic tube filled with cotton and sea sand.After adding 1 M HCl until the pH of the droplet became 1, the pH was adjusted to 5 with distilled water. Then add 1 M NaOH until the pH reaches 12 and thenThe pH was adjusted to 7 using distilled water. A solution prepared by dissolving 1,4,7,10-tetraazacyclododecane tetrahydrochloride (1.50 g, 4.72 mmol) in the smallest amount of distilled water was put therein, and droplets having a basic pH were collected.This solution is concentrated on a rotary evaporator andVacuum drying gave a yellow solid. Dissolve this in CHCl3, add Na2SO4 to dehydrate it, filter it with Nutche, wash it with a small amount of CHCl3, collect the filtrate, and concentrate it with a rotary evaporator.Vacuum dried and left in the refrigerator to give a yellow solid(0.772 g, Yield 95%).
91.3% With potassium hydroxide In water at 0 - 10℃; 5 Step 5: Preparation of cyclen 174g of cyclen · 4 hydrochloride was added to the reaction vessel, 100-200 ml of pure water was added, the temperature was raised to 80-100 ° C, and a solution of KOH (150-200 g) in water (150-200 ml) was added dropwise. After cooling to room temperature, crystals are precipitated. The ice-water bath is further cooled to 0-10 ° C, stirred for 1 hour, filtered, and the mother liquor is used to wash the filter cake. The filter cake is refluxed to remove water with toluene (500-800ml). Toluene (200-300 ml) was recrystallized to obtain 86 g of a white crystalline solid with a purity of 99.98% and a yield of 91.3%.
With potassium hydroxide
13.77 g With sodium hydroxide In toluene at 40℃; for 1h; Reflux; 1.4 In a 500 ml reaction flask equipped with a stirrer, a condenser, and a water separator, 38 g of IV (0.20 mol) was placed,25% sodium hydroxide 47. 5 mL (0.6 mol) (controlled internal temperature below 40 degrees), stirred for 1 hour,Add 142. 5mL toluene, heated to reflux, until the anhydrous separation, slightly cold (60 degrees), suction toluene overnight,Residue plus 25% sodium hydroxide 47. 5 mL (temperature, same as above),Add 142. 5mL toluene reflux to the water, static, take out the toluene solution,The combined toluene solution was concentrated at room temperature for about 57 mL and cooled to room temperature. The crystals were precipitated, filtered,The crude product was then recrystallized with 4 times (wet weight) of toluene,To give 13. 77 g of product (vacuum at room temperature). Content> 99% (GC).
12 g With sodium hydroxide In water; toluene d Step d, In a 500 mL reaction flask equipped with a stirrer, a condenser tube, and a water separator, 50 L of water and 50 g of water were successively added.Compound 4: 80g of sodium hydroxide with a concentration of 50%, stirred and crystallized, discharged, centrifuged, and the solid product was collected to obtain crude 15 g of cyclophanate, purified by toluene-water extraction, and the organic phase was collected and added to 142.5 mL. Toluene, heated to reflux, until no moisture is removed, cooled to 60°C, and the toluene was aspirated overnight. The residue was further added with 50% sodium hydroxide (temperature, ibid), and 142.5 mL of toluene was added to reflux to separate the water. Stir, suck out the toluene solution, combine the normal pressure of the toluene solution to concentrate about 57mL remaining at room temperature, cool to room temperature, crystallize out, and filter to obtain a crude product which is then recrystallized with 4 times (wet weight) toluene and concentrated to collect a white solid, which is dried under reduced pressure at 50°C. The product was obtained as 12 g of cyclosporine, yielding about 87.6%. . The reaction formula is as follows:
With sodium hydroxide In acetonitrile Inert atmosphere;

  • 2
  • [ 100-39-0 ]
  • [ 294-90-6 ]
  • [ 112193-83-6 ]
YieldReaction ConditionsOperation in experiment
98% Stage #1: 1,4,7,10-tetraazacyclododecan With tris(dimethylamino)borane; sodium hydride In toluene for 4h; Heating; Stage #2: benzyl bromide In toluene at 110℃; for 1h;
89% In acetonitrile for 1h; Heating;
89% With sodium carbonate In acetonitrile 1 1-Benzyl-1,4,7,10-tetraazacyclododecane EXAMPLE 1 1-Benzyl-1,4,7,10-tetraazacyclododecane A solution of benzyl bromide (4.96 g; 0.029 mol) in acetonitrile (50 ml) is added in 1 h to a solution of 1,4,7,10-tetraazacyclododecane (50 g, 0.29 mol) in acetonitrile (450 ml) at refluxing temperature of the solvent and under inert atmosphere. After 30 minutes from the end of the addition, the reaction mixture is cooled at 5 C. and part of the 1,4,7,10-tetraazacyclododecane in excess precipitate. After filtration, the reaction mixture is evaporated under reduced pressure. The residue, dissolved in 5% aqueous solution of sodium carbonate (200 ml), is extracted with toluene (3*200 ml). The organic phase is washed with water (100 ml), anhydrified (Na2 SO4) and evaporated to dryness. After crystallization by petrol ether (m.p. 40-60 C.), the desired product is obtained (6.8 g) as a white solid. Yield 89%. m.p.: 85 C. Titre: 98% (G.C.) 1 H-NMR (CDCl3): δ2.4 (m, 8H); 2.5 (m, 4H); 2.6 (bt, 4H); 3.4 (bs, 2H); 7.2 (bm, 5H). 13 C-NMR (CDCl3): δ44.90; 46.13; 46.98; 51.03; 59.04; 126.84; 128.11; 128.80; 138.74.
89% With sodium carbonate In acetonitrile 1 1-Benzyl-1,4,7,10-tetraazacyclododecane EXAMPLE 1 1-Benzyl-1,4,7,10-tetraazacyclododecane A solution of benzyl bromide (4.96 g; 0.029 mol) in acetonitrile (50 ml) is added in 1 h to a solution of 1,4,7,10-tetraazacyclododecane (50 g, 0.29 mol) in acetonitrile (450 ml) at refluxing temperature of the solvent and under inert atmosphere. After 30 minutes from the end of the addition, the reaction mixture is cooled at 5 C and part of the 1,4,7,10-tetraazacyclcdodecane in excess precipitate. After filtration, the reaction mixture is evaporated under reduced pressure. The residue, dissolved in 5% aqueous solution of sodium carbonate (200 ml), is extracted with toluene (3*200 ml). The organic phase is washed with water (100 ml), anhydrified (Na2 SO4) and evaporated to dryness. After crystallization by petrol ether (m.p. 40-60 C), the desired product is obtained (6.8 g) as a white solid. Yield 89%. m.p.: 85 C. Titre: 98% (G.C.) 1 H-NMR (CDCl3):δ2.4 (m, 8H); 2.5 (m, 4H); 2.6 (bt, 4H); 3.4 (bs, 2H); 7.2 (bm, 5H). 1 H-NMR (CDCl3):δ44.90; 46.13; 46.98; 51.03; 59.04; 126.84; 128.11; 128.80; 138.74.
84% In chloroform
63% With triethylamine In chloroform for 15h; Heating;
Yield given. Multistep reaction;
2.49 g Stage #1: 1,4,7,10-tetraazacyclododecan With hexacarbonyl molybdenum In dibutyl ether at 140℃; for 2h; Stage #2: With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 0.5h; Stage #3: benzyl bromide In N,N-dimethyl-formamide for 2h; Heating; Further stages.;

  • 3
  • [ 100-44-7 ]
  • [ 294-90-6 ]
  • [ 112193-83-6 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; air; hexacarbonyl molybdenum; potassium carbonate Yield given. Multistep reaction;
With triethylamine In chloroform for 20h; Inert atmosphere; Reflux;
  • 4
  • [ 52667-88-6 ]
  • [ 294-90-6 ]
YieldReaction ConditionsOperation in experiment
88% With sulfuric acid at 165℃;
87% Stage #1: cyclen tetratosylate With sulfuric acid at 100℃; for 0.05h; Microwave irradiation; Stage #2: With hydrogenchloride In water Stage #3: With sodium hydroxide In water
85% With sulfuric acid at 100 - 105℃; Heating; 30-48 h;
70% With hydrogen bromide; acetic acid; phenol at 50℃; for 14h;
70% With sulfuric acid at 100℃; for 39h;
70% With sulfuric acid at 100℃; for 48h;
60% With sulfuric acid at 130℃; for 72h;
60% Stage #1: cyclen tetratosylate With sulfuric acid at 170℃; for 6h; Stage #2: With hydrogen bromide In water Stage #3: With sodium hydroxide for 24h;
59% With sulfuric acid at 100℃; for 48h;
57% With sulfuric acid at 160℃; for 0.5h; Inert atmosphere; 1.1.4 1,4,7,10-tetraazacyclododecane (cyclen) Put a rotor in a 200 mL recovery flask,9.24 g (0.01171 mol) of cyclen · 4Ts and 46 mL of H 2 SO 4 were added, a reflux pipe equipped with a three way cock and a balloon was attached, vacuum drying and nitrogen substitution were carried out.The reaction vessel was immersed in an oil bath,Slowly raise the temperature to 160 ° C,The mixture was stirred at this temperature for 30 minutes. after that,Remove the oil bath, cool down to room temperature, remove the reflux tube, attach a 200 mL pressure equalizing dropping funnel,50 mL of EtOH was slowly added dropwise.Next, when 80 mL of Et 2 O was dropped slightly earlier, a dark brown solid precipitated, which was filtered and washed with EtOH and Et 2 O. This solid was dissolved in distilled water, filtered through celite, and the filtrate was concentrated with an evaporator to obtain a dark brown oily substance.When HCl and EtOH were added to the solution, a solid precipitated, which was washed and filtered with EtOH to obtain a pale brown solid of the desired hydrochloride(Yield 1.564 g, 42%).1.500 g (4.777 mmol) of this cyclen · 4 HCl was applied to an ion exchange column,The basic fractions were collected and concentrated to give a white solid.When CHCl 3 was added to this, impurities precipitated, so they were removed and again concentrated to obtain a white solid(Yield 0.4649 g, 57%).
54% With sulfuric acid at 110℃; for 72h;
33% With sulfuric acid at 115℃; for 28h;
With sulfuric acid
With sulfuric acid a) Richman and Atkins Procedure This is one of the most commonly used methods for the synthesis of cyclen, consisting of multistep protection-deprotection strategy.5-7 The key step of this method involves reaction of a preformed salt of a tritosylamide with sulfonate esters as leaving group in N,N-Dimethylformamide (DMF). Final separation of cyclen needs severe conditions to remove the tosyl protecting groups. For this purpose, 97% H2SO4 is used. This is a useful method provided that care is taken in the useof pure and dry starting materials. It has been reported to produce cyclen with a high yield (more than 60 %).

References: [1]Wilson, Jennifer M.; Giordani, Federica; Farrugia, Louis J.; Barrett, Michael P.; Robins, David J.; Sutherland, Andrew [Organic and Biomolecular Chemistry, 2007, vol. 5, # 22, p. 3651 - 3656].
[2]Wan, Fuxian; Li, Changcheng; Jiang, Lin; Li, Ying [Research on Chemical Intermediates, 2012, vol. 38, # 8, p. 2085 - 2096].
[3]Luk'yanenko, N. G.; Basok, S. S.; Filonova, L. K.; Kulikov, N. V.; Pastushok, V. N. [Chemistry of Heterocyclic Compounds, 1990, vol. 26, # 3, p. 346 - 349][Khimiya Geterotsiklicheskikh Soedinenii, 1990, # 3, p. 401 - 404].
[4]Lukyanenko, Nikolai G.; Basok, Stepan S.; Filonova, Lyubov K. [Journal of the Chemical Society. Perkin transactions I, 1988, p. 3141 - 3148].
[5]Luk'yanenko, N.G.; Basok, S.S.; Filonova, L.K. [Journal of Organic Chemistry USSR (English Translation), 1988, vol. 24, p. 1562 - 1571][Zhurnal Organicheskoi Khimii, 1988, vol. 24, # 8, p. 1731 - 1742].
[6]Montembault; Mouaziz; Blondeau; Touchard; Soutif; Brosse [Synthetic Communications, 1999, vol. 29, # 23, p. 4279 - 4294].
[7]Kohl, Stephan W.; Kuse, Katharina; Hummert, Markus; Schumann, Herbert; Mügge, Clemens; Janek, Katharina; Weißhoff, Hardy [Zeitschrift fur Naturforschung, B: Chemical Sciences, 2007, vol. 62, # 3, p. 397 - 406].
[8]Location in patent: scheme or table Sarma, Monima; Chatterjee, Tanmay; Das, Samar K. [Inorganic Chemistry Communications, 2010, vol. 13, # 10, p. 1114 - 1117].
[9]Pittet, Pierre-Andre; Frueh, Dominique; Tissieres, Veronique; Buenzli, Jean-Claude G. [Journal of the Chemical Society, Dalton Transactions, 1997, # 5, p. 895 - 900].
[10]Current Patent Assignee: DOSHISHA UNIVERSITY - JP2018/135304, 2018, A Location in patent: Paragraph 0039; 0040.
[11]Meunier, I.; Mishra, A. K.; Hanquet, B.; Cocolios, P.; Guilard, R. [Canadian Journal of Chemistry, 1995, vol. 73, # 5, p. 685 - 695].
[12]Das, Tapas; Chakraborty, Sudipta; Banerjeel, Sharmila; Samuel, Grace; Sarma; Venkatesh, Meera; Pillai [Journal of labelled compounds and radiopharmaceuticals, 2003, vol. 46, # 3, p. 197 - 209].
[13]Hormann, Jan; Perera, Chrischani; Deibel, Naina; Lentz, Dieter; Sarkar, Biprajit; Kulak, Nora [Dalton Transactions, 2013, vol. 42, # 13, p. 4357 - 4360].
[14]Ur Rashid, Haroon; Khan, Khalid; Yaseen, Muhammad; Hassan, Waseem; Naveed Umar, Muhammad [Revue Roumaine de Chimie, 2014, vol. 59, # 1, p. 27 - 33].
  • 5
  • [ 50-00-0 ]
  • [ 294-90-6 ]
  • [ 91987-74-5 ]
YieldReaction ConditionsOperation in experiment
64.8% With hydrogenchloride; phosphonic Acid In water at 110℃; for 2.5h;
  • 6
  • [ 50-00-0 ]
  • [ 294-90-6 ]
  • [ 76282-33-2 ]
YieldReaction ConditionsOperation in experiment
99% With formic acid; C19H26ClIrN3O(1+)*Cl(1-) In ethanol; water at 80℃; for 0.5h;
55% With formic acid In water for 30h; Heating;
With formic acid In water for 12h; Inert atmosphere;
  • 7
  • [ 683-57-8 ]
  • [ 294-90-6 ]
  • [ 157599-02-5 ]
YieldReaction ConditionsOperation in experiment
66% With triethylamine In ethanol at 80℃; for 4h; 1 To a 100 mL round bottom flask fitted with a reflux condenser and stir bar was added 1.4696 g Cyclen (8.5 mmol). 5.44 11 g of 2-bromoacetamide (39.4 mmol, 4.6 eq) was added with 4.5748 g triethylamine (44.9 mmol, 5.3 eq) in 30 mL absolute ethanol. The contents were refluxed for 4 hours at 80 °C, after which time a white precipitate formed in the flask. After cooling to room temperature, the precipitate was decanted and placed in a 250 mL round bottom flask, then dissolved in 200 mL of hot 80 % ethanol/20 % water. The volume was reduced by approximately 30 % on a roto-evaporator, then placed in the refrigerator overnight to produce white crystals. The remaining solvent was removed by filtration and the crystals were transferred to a 50 mL round bottom flask to dry on a Schlenk line under vacuum for several hours (66 % yield). ESI-MS: m/z = 401.3 (100 %), 402.3 (15 %) [M + H]+; 423.4 (25 %), 424.4 (< 10 %) [M + Na]+. 1H NMR (500 MHz, D20), ppm: 3.02 (s, amide pendent CH28H), 2.57 (s, Cyclen ring 16 H). 13C NMR (125 MHz, D20), ppm: 174.07 (carbonyl C),55.86 (amide CH2), 50.42 (ring CH2).
61% With triethylamine In ethanol for 4h; Heating;
38% With triethylamine In ethanol for 4h; Reflux;
With potassium carbonate In acetonitrile
With triethylamine In ethanol

  • 8
  • [ 73391-96-5 ]
  • [ 294-90-6 ]
  • [ 132930-14-4 ]
YieldReaction ConditionsOperation in experiment
30% With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 24h;
  • 10
  • [ 5292-43-3 ]
  • [ 294-90-6 ]
  • [ 137145-75-6 ]
YieldReaction ConditionsOperation in experiment
94% In chloroform at 20℃; for 1h;
58% In acetonitrile for 1h; Heating;
50% In chloroform at 0℃; for 2h; Compound HHY-261 To a stirred solution of 1,4,7j0-tetraazacyclododecane (cyclen) (3.44 g, 20mmol) in CHC13 (40 mL) was added t-butylbromoacetate (0.5 eq) in CHC13 (10 mL) within1 h at 0°C. Stirring was continued for an additional hour. The solution became cloudy(cyclenHBr). TLC control showed complete disappearance of the t-butylbromoacetate.The precipitate was filtered and the filtrate concentrated in vacuo. The resulting oil waspurified by HPLC (95 % H20- 60% CH3CN) to yield HHY-261 (1.43 g, 50 %) as acolorless (Tetrahedron Letters. 2006, 47, 5985-5988). ESI-MS found: [M+H] = 2873.
33.3% With caesium carbonate In acetonitrile at 25℃; for 6h;
27% With potassium carbonate In acetonitrile at 5060℃; for 5h; Inert atmosphere;
In chloroform at 20℃; for 14h; Under N2; t-butyl bromoacetate was added within 7 h;

  • 11
  • [ 79-11-8 ]
  • [ 294-90-6 ]
  • [ 114873-37-9 ]
YieldReaction ConditionsOperation in experiment
69.58% With sodium hydroxide at -4 - 50℃;
With water at 50℃; pH 8.0;
With sodium hydroxide In water at -4℃;
With lithium hydroxide monohydrate In water at -5 - 65℃; for 5h; 1; 2; 4 Example 2 Take 100g of ring tempering (M1), add 200mL of purified water and stir to dissolve.Another 165 g of chloroacetic acid was dissolved in 160 mL of purified water, and 80 g of lithium hydroxide monohydrate was added at -5 ° C, and dissolved by stirring.The lithium chloroacetate solution was added dropwise to a ring of ringing (M1) solution at room temperature.At the end of the dropwise addition, the temperature was raised to 65 ° C, and about 50 g of lithium hydroxide monohydrate was added in portions over 3 hours to control the pH of the reaction system to be greater than 9.The reaction was continued for 2 hours, the reaction was completed, the temperature was lowered to room temperature, and the pH was adjusted to 3.5 with hydrochloric acid.Slowly add 2000mL of ethanol, a large amount of solids are precipitated, and filtered.The filtrate solvent was removed under reduced pressure to give the crude product DO3A 130g (HPLC purity 82%).

  • 12
  • [ 542-81-4 ]
  • [ 294-90-6 ]
  • [ 202334-68-7 ]
YieldReaction ConditionsOperation in experiment
72% With potassium carbonate In acetonitrile at 40℃; for 24h;
51% With potassium carbonate In acetonitrile at 60℃; for 24h; Inert atmosphere;
  • 13
  • [ 294-90-6 ]
  • [ 17329-87-2 ]
  • 1-(N-(4-nitrophenyl)carbamoylmethyl)-1,4,7,10-tetraazacyclododecane [ No CAS ]
  • 14
  • [ 294-90-6 ]
  • [ 112193-83-6 ]
YieldReaction ConditionsOperation in experiment
In acetonitrile Heating; Yield given;
  • 15
  • [ 294-90-6 ]
  • [ 137145-75-6 ]
YieldReaction ConditionsOperation in experiment
In acetonitrile Heating; Yield given;
  • 16
  • [ 204253-07-6 ]
  • [ 294-90-6 ]
  • [ 204252-89-1 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate 1.) Bu2O, reflux, 2 h; 2.) DMF, 60 deg C, 4 h; Yield given. Multistep reaction;
  • 17
  • [ 121221-07-6 ]
  • [ 294-90-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With potassium iodide In N,N-dimethyl-formamide at 80℃; for 12h;
  • 18
  • [ 100-39-0 ]
  • [ 294-90-6 ]
  • [ 112193-83-6 ]
  • [ 183160-82-9 ]
YieldReaction ConditionsOperation in experiment
1: 81% 2: 1% With potassium carbonate In acetonitrile at 55 - 60℃; for 4h;
  • 19
  • [ 79-11-8 ]
  • [ 294-90-6 ]
  • [ 60239-18-1 ]
YieldReaction ConditionsOperation in experiment
88% With sodium hydroxide In water at 70℃; for 30h;
82.7% With (-)-cycleanine; sodium hydroxide In water at 80 - 85℃; Large scale; 1 Example 1 11.8 kg of chloroacetic acid along with 121 purified water were added to a 100 L reactor, stirred and dissolved, and 151 water in which 5 kg of sodium hydroxide was dissolved was added in an ice bath, 3.2kg of the cycleanine suspended in 6 l water and added to the reaction, the temperature was raised to 80~85 °C, 6L of water with 5.2kg of sodium hydroxide was added drop wise to control the pH of the reaction system at 10~11, reacted overnight, after cooling to room temperature, 10.41 concentrated hydrochloric acid was added drop wise, the pH was adjusted to 2 to 2.5, stirred and crystallized, and the filter cake was collected by filtration and dried to obtain 7.5 kg of crude D0TA. The content of the compound of formula II was about 3.1%. 7.5kg of crude DOTA, 18 kg of purified water was added to the 50L reactor, after heating and stirred to dissolve, crystallization was cooled, filtered, washed, dried to obtain D0TA 6.21kg, the yield was 82.7 %, and the salt content was 2%, formula II compound content was 0.05%.
82.7% With sodium hydroxide In water at 80 - 85℃; Industrial scale; 1 Example 1 Add 11.8kg of chloroacetic acid and 12L of purified water to a 100L reactor, stir to dissolve, add 15L of water with 5kg of sodium hydroxide dissolved in an ice bath, suspend 3.2kg of cyclen in 6L of water and add to the reaction. 8085,Drop 6L water with 5.2kg sodium hydroxide dissolved in it,Control the pH of the reaction system at 10-11, react overnight,After cooling to room temperature, 10.4L concentrated hydrochloric acid was added dropwise,Adjust the pH to 22.5, stir to crystallize, filter the filter cake, and dry to obtain 7.5 kg of crude DOTA.Add 7.5 kg of DOTA crude product and 18 kg of purified water into a 50L reactor, heat and stir to dissolve, cool to crystallize, filter, wash, and dry to obtain 6.21 kg of DOTA with a yield of 82.7%, and the content of salt is 2%.
80% With hydrogenchloride In water at 80℃;
78% Stage #1: chloroacetic acid; 1,4,7,10-tetraazacyclododecan With hydrogenchloride; potassium hydroxide In water at 75℃; for 24h; Reflux; Stage #2: With hydrogenchloride
75.8% With lithium hydroxide monohydrate; water at 0 - 30℃; for 24h; Embodiment 6 Cyclen (17.27 g, 100 mmol), lithium hydroxide monohydrate (36.92 g, 880 mmol) and water (80 mL) were added into a three-necked flask (1000 mL) at 0-10° C. A solution of choroacetic acid (41.58 g, 440 mmol) in water (30 mL) was added at 5-15° C. The mixture was warmed to 20-30° C. and reacted for 24 hours. No surplus of the raw material cyclen was detected by TLC. 36% hydrochloric acid (44.6 g, 440 mmol) and ethanol (600 mL) were added to the system for solids precipitation, followed by filtration. The resulting solids were purified by recrystallization with ethanol/water (volume ratio 3:1) and dried at 60° C. to obtain DOTA. Yield: 75.8%, HPLC: 99.8%, residue on ignition: 0.08%, moisture: 7.50%.
74% With hydrogenchloride; potassium hydroxide In water at 75℃;
With sodium hydroxide In water at 25℃; for 20h; 1 Example 1 - Kinetic study for DOTA production during the step a) of the process Example 1 - Kinetic study for DOTA production during the step a) of the process This example illustrates the kinetics of step a) of the process for production of DOTA according to the present invention. The reaction was conducted for 72h at a temperature of 25°C, using chloroacetic acid as the halo-acetic acid (4.3 eq.) and sodium hydroxide as a base (11.0 eq.) in water (12x - 12 parts of water for 1 part of initial amount of cyclen in weight) and samples were taken at different times for in-process control analysis via HPLC- chromatography (see above) . The results are shown in Table 1 as surface area % in the HPLC chromatograms and the conversion value (%) is found according to the following formula: Conversion (%) = 100% - X wherein X is the amount of cyclen. Measured impurities comprise unreacted alkylating acid, intermediate cyclen derivatives and counterions introduced by the halo-acetic acid and by the treatment with a base . Table 1 : Kinetic study data *RRT = Relative Retention Time These results show that in the settled conditions the reaction is completed after 20h, i.e at that time the conversion rate is 100%, which means that the starting material was completely consumed and therefore, that the process of the present invention can be carried out at temperatures as low as 20 °C.
With sodium hydroxide In water at 5 - 25℃; for 20h; Large scale; 3 3. Preparation of DOTA to be purified 3. Preparation of DOTA to be purifiedSeven batches of DOTA were prepared. Batch B-01 was prepared by adding chioroacetic acid (54.86 Kg, 580.48 mol) to a solution of 1,4,7,10- tetraaza cyclododecane (20 Kg, 116.1 mol) in water (120 L) and the reaction mixture was cooled to 5±5°C. A solution of sodium hydroxide (48.77 Kg in 120 L water, 1219 mol) was added slowly to the reaction mass by maintaining the internal temperature at 10±5°C. The reaction mass was slowly warmed to 25±5°C and stirred for 20 h. The obtained DOTA batch B-01, according to IPC has a DOTA content of 75.53 (area)%, contains also an intermediate compound (at retention time of 0.84 from the retention time of DOTA) of 1.2 (area)% and a cyclene content of 0.0%.
183 g With potassium hydroxide In water at 80℃; for 24h; 2.1 Step 1: Preparation of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) To the three-necked flask was added 1,4,7,10-tetraazacyclododecane (100 g, 0.58 mol)10 ml of deionized water, stirred, 30% KOH solution was added dropwise,The pH was adjusted to 8.5 and then chloroacetic acid (263 g, 2.78 mol) was added,And then 30% KOH solution to adjust the pH to 8.5,Heated to 80 ° C for 24 h, during which the pH was maintained between 8.5 and 9.After the reaction, cooling, adding concentrated hydrochloric acid to adjust the pH to 2, a white precipitate produced, filtered. The filter cake was recrystallized from a water-ethanol solution and the resulting crystals were washed with ethanol, ether, dried,183 g of DOTA crystals was obtained in a yield of 78%.
With sodium hydroxide In water at 80℃;
With sodium hydroxide In water at 80℃; 1 Example 1. Synthesis of raw tetraxetan A 125 g/L solution of cyclen (1 eq.) in water is prepared. Then chloroacetic acid (4.5 eq.) is added. The mixture is heated to 80eC and the pH of the reaction is adjusted to 8, adding sodium hydroxide using a pH controller. When the reaction is completed, the pH is raised to 10 maintaining the temperature for the necessary time. The reaction mixture is then cooled to 65°C and then concentrated HCI is added until pH

References: [1]Das, Tapas; Chakraborty, Sudipta; Banerjeel, Sharmila; Samuel, Grace; Sarma; Venkatesh, Meera; Pillai [Journal of labelled compounds and radiopharmaceuticals, 2003, vol. 46, # 3, p. 197 - 209].
[2]Current Patent Assignee: JIANGSU HENGRUI MEDICINE - CN108658882, 2018, A Location in patent: Paragraph 0058-0061.
[3]Current Patent Assignee: JIANGSU HENGRUI MEDICINE - CN111375071, 2020, A Location in patent: Paragraph 0005; 0058-0061.
[4]Dong, Zhiqiang; Chen, Chenli; Chen, Lingfang; Sun, Mingli; Zhan, Junzheng; Zhou, Shen; Cao, Lijia; Liu, Jianyu; Bai, Shuming; Jie, Jialong; Su, Hongmei; Gao, Song; Zhou, Linan [Chemical Science, 2025, vol. 16, # 37, p. 17276 - 17286].
[5]Wu, Fengcheng; Ye, Gang; Yi, Rong; Sun, Taoxiang; Xu, Chao; Chen, Jing [Dalton Transactions, 2016, vol. 45, # 23, p. 9553 - 9564].
[6]Current Patent Assignee: VIWIT PHARMACEUTICAL - US2020/347023, 2020, A1 Location in patent: Paragraph 0079; 0080.
[7]Simke, Julian; Böckermann, Till; Bergander, Klaus; Klabunde, Sina; Hansen, Michael Ryan; Ravoo, Bart Jan [Organic and Biomolecular Chemistry, 2021, vol. 19, # 10, p. 2186 - 2191].
[8]Current Patent Assignee: T2PHARMA DE - WO2014/114664, 2014, A1 Location in patent: Page/Page column 28-29.
[9]Current Patent Assignee: T2PHARMA - WO2015/117911, 2015, A1 Location in patent: Paragraph 0081; 0082; 0083; 0084.
[10]Current Patent Assignee: ZHEJIANG DADE PHARMACEUTICAL GROUP - CN104447598, 2017, B Location in patent: Paragraph 0096; 0098; 0099.
[11]Nielsen, Lea Gundorff; Sørensen, Thomas Just [Inorganic Chemistry, 2019].
[12]Current Patent Assignee: JUSTESA IMAGEN U - WO2021/250163, 2021, A1 Location in patent: Page/Page column 8.
  • 20
  • [ 5292-43-3 ]
  • [ 294-90-6 ]
  • [ 507475-91-4 ]
YieldReaction ConditionsOperation in experiment
84% With triethylamine In chloroform at 20℃; for 7h;
39% Stage #1: 1,4,7,10-tetraazacyclododecan With N-ethyl-N,N-diisopropylamine In chloroform for 0.25h; Inert atmosphere; Stage #2: bromoacetic acid <i>tert</i>-butyl ester In chloroform for 12.5h;
39% With N-ethyl-N,N-diisopropylamine In chloroform for 12h;
70 % With triethylamine In dichloromethane at 25℃; 2 Example 2 Dissolve 1.72g Cyclen in 200mL dichloromethane, add 5.05g triethylamine, and stir for 15min under ice bath. Dissolve 3.9 g of tert-butyl bromoacetate in 20 mL of dichloromethane, then slowly add the tert-butyl bromoacetate solution to the Cyclen solution dropwise for 30 minutes. After the dropwise addition, react at 25°C for 24h. The solvent was distilled off under reduced pressure to obtain a yellow oily crude product. Purification by 300-400 mesh silica gel column chromatography (dichloromethane:methanol=30:1) gave 2.81 g of a colorless oily substance, namely compound 2 (yield 70%)

  • 21
  • [ 88404-25-5 ]
  • [ 294-90-6 ]
  • [ 782447-39-6 ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate In dichloromethane at 20℃; for 72h;
  • 22
  • [ 10254-07-6 ]
  • [ 294-90-6 ]
  • [ 740846-04-2 ]
YieldReaction ConditionsOperation in experiment
71% With chloroform; triethylamine
  • 23
  • [ 10254-07-6 ]
  • [ 294-90-6 ]
  • [ 740845-92-5 ]
YieldReaction ConditionsOperation in experiment
81% With chloroform; triethylamine
  • 24
  • [ 95331-76-3 ]
  • [ 294-90-6 ]
  • [ 861929-72-8 ]
YieldReaction ConditionsOperation in experiment
91% With potassium carbonate In acetonitrile at 70℃;
  • 25
  • [ 5349-24-6 ]
  • [ 294-90-6 ]
  • [ 832079-71-7 ]
YieldReaction ConditionsOperation in experiment
76% With caesium carbonate; potassium iodide In N,N-dimethyl-formamide at 70℃; for 18h;
  • 26
  • [ 294-90-6 ]
  • [ 80650-46-0 ]
  • [ 853946-30-2 ]
YieldReaction ConditionsOperation in experiment
86% With caesium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 64h;
  • 27
  • [ 108-30-5 ]
  • [ 294-90-6 ]
  • [ 870994-56-2 ]
YieldReaction ConditionsOperation in experiment
90% for 2h;
  • 28
  • [ 294-90-6 ]
  • [ 149979-14-6 ]
  • [ 913972-22-2 ]
YieldReaction ConditionsOperation in experiment
87% With caesium carbonate; potassium iodide In acetonitrile for 72h; Heating;
87% With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 70℃; for 24h; Inert atmosphere; 1.b Preparation of DOTA-4EDA-BOC The cyclen is 0.25g (1.45mmol), CA-EDA-BOC 1.60g (6.76mmol),Potassium carbonate 1.2g(8.7 mmol), 1.2 g (7.23 mmol) of potassium iodide dissolved in 8 mL DMF,The reaction solution was heated under magnetic protection at 70 ° C for 24 h under nitrogen.The reaction solution was then transferred to a separatory funnel and dissolved in 100 mL of chloroform.Wash with 3 x 50 mL of water,The organic layer is rotary evaporated to obtain a DOTA-4EDA-BOC solid product.The yield was 87%.
86.9% With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 70℃; for 24h; Inert atmosphere;
  • 29
  • [ CAS Unavailable ]
  • [ 294-90-6 ]
  • [ 156970-79-5 ]
YieldReaction ConditionsOperation in experiment
78% With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃;
  • 30
  • [ 13139-12-3 ]
  • [ 294-90-6 ]
  • [ 913542-69-5 ]
YieldReaction ConditionsOperation in experiment
100% In chloroform at 20℃;
100% In chloroform
100% In chloroform at 20℃; for 31h; 4.3. 1,7-Bis[3,5-di(bromomethyl)benzyl]-4,10-di(tert-butoxycarbonyl)-1,4,7,10-tetraazacyclododecane (11) N-(tert-Butoxycarbonyloxy)succinimide (2.50 g, 11.62 mmol) inchloroform (30 mL) was added dropwise into the solution of1,4,7,10-tetraazacyclododecane (1.00 g, 5.80 mmol) in CHCl3(50 mL) during 7 h. The reaction mixture was stirred 24 h at roomtemperature and the solvent was removed under reduced pressure. The residue was suspended in aqueous NaOH (3 M, 50 mL) and theaqueous phase was extracted with CHCl3 (3 50 mL). The combinedextracts were dried with K2CO3 and evaporated to drynessto give 1,7-bis(tert-butoxycarbonyl)-1,4,7,10-tetraazacyclododecane(10) in quantitative yield.1,3,5-Tris(bromomethyl)benzene (7.65 g, 21.62 mmol) was dissolvedin CHCl3 (150 mL) and Na2CO3 (1.71 g, 16.15 mmol) wasadded. Compound 10 (1.08 g, 2.90 mmol) in CHCl3 (50 mL) wasadded dropwise into the reaction mixture during 11 hours at52 C. The reaction mixture was refluxed for 3 days at 62 C,filtrated, and evaporated to dryness. The residue was purified bysilica gel chromatography (40-70% EtOAc in hexane), giving 11 in27% yield (0.722 g). 1H NMR (500 MHz, CDCl3) d 7.33 (s, 6H), 4.45(s, 8H), 3.71 (s, 4H), 3.21-3.57 (m, 8H), 2.55-2.68 (m, 8H), 1.27(s, 18H). 13C NMR (100 MHz, CDCl3) dppm 155.8, 140.8, 138.5,129.9, 128.3, 79.3, 59.5, 55.2, 46.1, 32.9, 28.4. HRMS(ESI): obsd.921.0840 [M+H]+, Calcd. 921.0795 [M+H]+.
84% In chloroform at 20℃; for 48h;
80% With triethylamine In dichloromethane for 6h; 1.2.1 (1) Synthesis of Compound 4: 1,4,7,10-Tetraazacyclododecane 1c (1.72 g, 1.0 equiv.) and triethylamine (TAE, 2.17 g, 2.2 equiv.) were added to a round-bottom flask and dissolved in dichloromethane. Separately, tert-butyl N-succinimidyl carbonate 1d (Boc-Osu, 4.59 g, 2.2 equiv.) was dissolved in dichloromethane and added to a constant pressure dropping funnel. The mixture was added dropwise to the round-bottom flask in an ice-water bath. After 6 h of reaction in the ice-water bath, the reaction was stopped and the solvent was removed by rotary evaporation. The crude product was separated by silica gel column chromatography using PE/EA = 1:1 (v/v) as the eluent to obtain a white solid, Compound 4, in an 80% yield.
In chloroform at 20℃;
With sodium hydroxide In chloroform 4 Synthesis of 1,7-bis(tert-butoxycarbonyl)-1,4,7,10-tetraazacyclododecane Synthesis of 1,7-bis(tert-butoxycarbonyl)-1,4,7,10-tetraazacyclododecane Cyclen (1.05 g) was dissolved in chloroform (50 mL), to which N-(tert-butoxycarbonyloxy)succinimide (2.62 g) was added, followed by stirring at room temperature. After 48 hours of stirring, the solvent was distilled off under reduced pressure. The resulting residue was dissolved in chloroform (50 mL), washed with an aqueous solution of sodium hydroxide, and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the resulting product was dried in a vacuum to give the title compound (2.27 g).
In chloroform
80 % With triethylamine In dichloromethane Cooling with ice; 1.1.2.1 1.2 Synthesis of 4N2R (1) Synthesis of compound 4:Add 1,4,7,10-tetraazacyclododecane 1c (1.72 g, 1.0 equiv.) and triethylamine (TAE, 2.17 g, 2.2 equiv.) into the round-bottomed flask,Soluble in methylene chloride.Alternatively N-succinimide tert-butyl carbonate1d (Boc-Osu, 4.59 g, 2.2 equiv.) dissolved in dichloromethane,Add constant pressure dropping funnel,Add dropwise to the above round bottom flask in an ice water bath.After reacting in an ice-water bath for 6 hours,stop reacting,The reaction solvent was removed by rotary evaporation.The crude product was separated by silica gel column chromatography,The eluent is PE / EA = 1:1 (V/V),The white solid product was purified,That is, compound 4, with a yield of 80%.
80 % With triethylamine In dichloromethane Cooling with ice; 1.1.2.1 1.2 Synthesis of 4N2R (1) Synthesis of compound 4:Add 1,4,7,10-tetraazacyclododecane 1c (1.72 g, 1.0 equiv.) and triethylamine (TAE, 2.17 g, 2.2 equiv.) into the round-bottomed flask,Soluble in methylene chloride.Alternatively N-succinimide tert-butyl carbonate1d (Boc-Osu, 4.59 g, 2.2 equiv.) dissolved in dichloromethane,Add constant pressure dropping funnel,Add dropwise to the above round bottom flask in an ice water bath.After reacting in an ice-water bath for 6 hours,stop reacting,The reaction solvent was removed by rotary evaporation.The crude product was separated by silica gel column chromatography,The eluent is PE / EA = 1:1 (V/V),The white solid product was purified,That is, compound 4, with a yield of 80%.

  • 31
  • [ 49590-51-4 ]
  • [ 294-90-6 ]
  • [ 922725-82-4 ]
YieldReaction ConditionsOperation in experiment
78% With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃;
78% With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 48h; Inert atmosphere;
78% With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 48h; Inert atmosphere;
  • 32
  • [ 17374-48-0 ]
  • [ 294-90-6 ]
  • [ 937200-96-9 ]
  • [ 937200-98-1 ]
YieldReaction ConditionsOperation in experiment
1: 60% 2: 20% In tetrahydrofuran at 20℃;
1: 60% 2: 15% In tetrahydrofuran at 40℃; for 24h;
  • 33
  • [ 294-90-6 ]
  • [ 112193-75-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: H2O / pH 7 3: concentrated HCl / 65 h
Multi-step reaction with 3 steps 1: 88 percent / pH 2-3 2: iPr2NEt / acetonitrile / 20 h / 60 °C 3: aq. HCl / 24 h / Heating
  • 34
  • [ 10254-07-6 ]
  • [ 294-90-6 ]
  • [ 794460-95-0 ]
YieldReaction ConditionsOperation in experiment
81% Stage #1: N-benzhydryl-2-chloroacetamide; 1,4,7,10-tetraazacyclododecan With triethylamine In chloroform for 2.5h; Stage #2: With potassium carbonate In chloroform for 15h; 2 3.3 equivalents of N-2-CHLOROETHANOYL-DIPHENYLMETHYLAMINE (1.98 g, 7.6 mmol) dissolved in 10.0 mL anhydrous chloroform was added dropwise to a mixture of 1,4, 7,10- tetraazacyclododecane (cyclen) (400.0 mg, 2.32 mmol) and 10.0 equivalents of triethylamine (2.3 g, 23.2 mmol) in 40 ML anhydrous chloroform under an argon atmosphere for about half an hour. The reaction mixture was stirred for another 2 hours, and 0.5 equiv. of anhydrous K2CO3 was added. After a further 15 hours of reaction, the resulting solution was washed by water (3 x 40 ML) and the organic phase was dried by anhydrous Na2SO4. Removing the solvent under vacuum gave the light yellow solid. The crude product was purified by flash chromatography on aluminium oxide (dichloromethane/methane = 200: 10 (v/v), Rf= 0.30) to give tris-[(diphenyl) methylcarbamoylemethyl]-1, 4,7, 10-tetraazacyclododecane as a colourless oil (1.58 g, 1.88 mmol), yield 81%.1HNMR (400 MHz, CDCl3) ; δ 7.22-7.06 (30H, m), 6.18 (2H, d, J (H,H) = 6.3 Hz), 5.97 (1H, d, J (H,H) = 6.3 Hz), 3.27-3. 17 (6H, m), 2.72-2.25 (16H, br, M) ; 13CNMR (100 MHz, CDCl3) : δ 171.5 (2 x C), 171.3 (C), 141.8 (4 x C), 141.7 (2 x C), 129.1 (12 x CH), 128.1 (12 x CH), 127.8 (6 x CH), 59.7 (3 x CH), 58. 2 (3 x CH2), 51.3 (2 x CH), 51.1 (2 x CH2), 49.2 (2 x CH2), 47.5 (2 x CH2) ; ESI-MS m/z 842 (M+H)+; HRFAB-MS /z 842.4769 (M+H) + [Calcd. for C53H60N7O3 (M+H)+, 842.4758]. Anal. Calcd. FOR C53H60N703C1 : C, 72.46 ; H, 6. 88 ; N, 11.16.-found : C, 72. 25 ; H, 6.65 ; N, 11.12.
  • 35
  • [ 16644-30-7 ]
  • [ 294-90-6 ]
  • [ 690253-70-4 ]
YieldReaction ConditionsOperation in experiment
~ 12% With triethylamine; In tetrahydrofuran; A compound having the structure shown as the final product in the scheme detailed in FIG. 4 was synthesized and characterized. Reaction step (1) (shown in isolation in FIG. 6) proceeds well and the product was characterized by 1H NMR spectroscopy (peak obtained at MW=214). This product was readily purified by recrystallization from hot n-hexane. The yield of this reaction in our hands was not established. The literature value is 89% isolated yield. L. D. Taylor and R. B. Davis, J. Org. Chem. 1963, 28, 1713. [0074] Reaction step (2) (shown in isolation in FIG. 7) also proceeded and the crude product was purified by recrystallization from ethanol/tetrahydrofuran. Small, square-shaped orange crystals were obtained over a period of two days in ca. 12% yield. Analysis of these crystals via 1H NMR spectroscopy suggests that their crystal structure may contain tetrahydrofuran (see FIG. 8). Mass spectroscopy yielded an m/z peak at 352. Further addition of tetrahydrofuran to the ethanol mixture yielded a second crop of similar crystals. However, this second crop was coated in orange-colored viscous oil, characteristic of material that had come out of solution too quickly. This material is to be further recrystallized to improve product yield. [0075] Reaction step (3) (shown in isolation in FIG. 9) was carried out under reflux (approximately 80 C.) proceeded well and yielded a solid product as expected. Previous attempts to synthesize this compound have yielded viscous oil. Purification of the product from reaction (2) appears to lead to a purer product from reaction (3) as we obtained a solid instead of an oil. This product was analyzed by 1H NMR and by ES mass spectral analysis: FW ca. 506, [M]+504 (100%). [0076] Reaction step (4) (shown in isolation in FIG. 10) was conducted overnight at pH=10-11. However, the pH dropped to a value of 9 after 24 h. Thus, the pH was again raised to a value of ca. 10 and allowed to react for a further 24 h, during which time the reaction mixture maintained its pH value of ca. 10. It appears that at least 48 hours are necessary for the reaction to go to completion as indicated by the lack of further pH change. ES mass spectral analysis indicated a prominent peak at 701 (expected mass of the ligand+Na+). [0077] Reaction step 5 (i.e., the final reaction step shown in FIG. 4) involves the insertion of the metal to the macrocycle. The sample was run through a Chelex 100 column after first neutralizing the reaction mixture to pH=7. However, upon eluting with water, only pale yellow oil was obtained. This did not display the characteristic absorbances of ca. 510 and 550 nm upon exposure to UV-light irradiation. In addition, it was observed that a band of purple-colored material was trapped at the top of the Chelex column. Various solvents were used to try to pass this band through the column, and ethanol and chloroform each were found to be effective to elute the product. This purple-colored material displayed characteristic color changes expected for the final product. UV irradiation (described in the following example) produced a product with absorbances at ca. 510 and 550 nm. Irradiation with white light eliminates these absorbance peaks. Mass spec for the product from step 5 yielded a peak at 835 and also peak at 678 (representing either free ligand or artifactual dissociation of product during electrospray).
  • 36
  • [ 22989-38-4 ]
  • [ CAS Unavailable ]
  • [ 294-90-6 ]
  • [ 515119-62-7 ]
YieldReaction ConditionsOperation in experiment
2.54 g (75%) In chloroform 4 Synthesis of N-(6-Methyl-2-quinolylmethyl)-1,4,7,10-tetraazacyclododecane (4, R1=quinolyl, R3=methyl) Example 4 Synthesis of N-(6-Methyl-2-quinolylmethyl)-1,4,7,10-tetraazacyclododecane (4, R1=quinolyl, R3=methyl) To a stirring solution of cyclen (3.52 g, 0.0204 mol) in chloroform (525 mL) was added 2-(Chloromethyl)-6-methylquinoline (3) (2 g, 0.0104 mol). The reaction was then allowed to stir until completion as determined by TLC, concentrated and purified on silica using a gradient elution system starting with 50:1 CHCl3:MeOH; 150:4:1 CHCl3:MeOH:NH4OH; 100:4:1; 50:4:1; and finally with 20:4:1 to afford 2.54 g (75%) of a pale yellow oil. H1 NMR (CDCl3): δ2.35-3.15 (m, 22H), 3.87 (s, 2H), 7.33-7.42 (m, 2H), 7.58-7.62 (d, 1H), 7.94-8.07 (m, 2H).
  • 37
  • [ 3913-23-3 ]
  • [ 294-90-6 ]
  • N-(2-methoxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane [ No CAS ]
YieldReaction ConditionsOperation in experiment
79% In chloroform; EXAMPLE E Preparation of N-(2-methoxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane. To a stirred chloroform solution (20 ml) containing 2.9 g of 1,4,7,10-tetraazacyclododecane (16.8 mmole) was added a chloroform solution (20 ml) containing 2.1 g of <strong>[3913-23-3]2-methoxy-5-nitrobenzyl bromide</strong> (8.5 mmole) in one portion. After stirring at room temperature for three hours the reaction mixture was filtered and the filtrate concentrated (in vacuo) to give a residue which was chromatographed (silica, Solvent System 3). The monoalkylated product was isolated in 79 percent yield (MP=154-156 C.), and characterized by: 13 C NMR (CDCl3) 162.47, 140.63, 127.92, 125.49, 124.53, 109.91, 55.88, 53.25, 50.90, 47.18, 45.45, 45.29.
  • 38
  • [ 5292-43-3 ]
  • [ 294-90-6 ]
  • [ 137145-75-6 ]
  • [ 122555-91-3 ]
  • [ 507475-91-4 ]
YieldReaction ConditionsOperation in experiment
With triethylamine In methanol; dichloromethane for 12 - 16h; It was discovered that if a mixture of alkylated D02A, DOlA as free bases were allowed to evaporated in a crystallizing dish form methanol/water mixes a white solid would form which is presumable the carbonate salt from the amine reacting with carbon dioxide in water as is known for certain amines. We discovered that the DOlA carbonate salt was very soluble in methanol and thus could be removed from a mixture of DOlA and D02A as their carbonate salts. We then adjusted the experimental alkylation conditions to take advantage of this separation. A 24.4 MMOLE portion of cyclen was dissolved in 60 ML of methylene chloride and 20 mL of MEOH. Again 4 eq of triethylamine (13.69mL) was added all at once.. Then via syringe 3.61 ML (24.4 MMOLES ; 1 equivalent) of t-butyl bromoacetate was added was added all at once. After 12-16 hours the reaction solution was diluted with 40 mL of methylene chloride and extracted with 80 mL of IN NAOH. The aqueous layer was back extracted with 2X80 mL of methylene chloride and the combined organic layers were dried over sodium sulfate and rotoevaporated to give 5.72 g of clear viscous oil (82% of theory).. This 5.72 g was dissolved in 75 mL of MEOH and diluted with 90 mL of water. The solution was poured into a crystallizing dish and allowed to evaporated in a hood until about 1/6TH of original volume (about 38 grams total weight) remained (mostly water) and a lot of white solid was present. The solid was filtered and washed with 20 mL water and then dried under vacuum to give 4.3964 g of white solid. By LC-MS analysis this material is 92% bis substititued (in the 1,4 substitution pattern) with 6% mono substituted and only 2% trisubstituted. This form is not suitable for alkylation reactions as it is the carbonic acid salt of the free amine. To convert to the free base a 1.6881 gram portion was dissolved in 12 mL of 1 N HCl (about 3 equivalents) and some bubbling as the carbonate is neutralized was noted. Then 2 equivalents (relative to acid added= 24 MMOLES) of NAOH (6 ML of 4 M NAOH) was added and the free base oils out. The free base was extracted with four 20 mL extractions of methylene chloride. The combined organic layers were dried over sodium sulfate and then decanted and rotoevaporated to yield 1.603 g of pale yellow oil LCMS analysis by spiking this free-base product with an authentic sample of 1, 7- substituted material showed two peaks indicating the major product we isolated is indeed the 1,4-bis substituted product (showing a [M+H] + of 401 m/z.).
  • 39
  • [ 6132-45-2 ]
  • [ 294-90-6 ]
  • [ 1082207-97-3 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane at 20℃; for 12h;
  • 40
  • [ 2895-21-8 ]
  • [ 294-90-6 ]
  • [ 1105681-51-3 ]
  • 41
  • [ 5292-43-3 ]
  • [ 294-90-6 ]
  • [ 137145-75-6 ]
  • [ 122555-91-3 ]
  • [ 585531-74-4 ]
YieldReaction ConditionsOperation in experiment
1: 47% 2: 451 mg 3: 0.3% In chloroform at 0 - 20℃;
  • 42
  • [ 87165-53-5 ]
  • [ 294-90-6 ]
  • [ 1206717-16-9 ]
YieldReaction ConditionsOperation in experiment
81% With N-ethyl-N,N-diisopropylamine In acetonitrile at 60℃; for 24h; Inert atmosphere;
  • 43
  • [ 3792-04-9 ]
  • [ 294-90-6 ]
  • [ 1211942-04-9 ]
  • 45
  • [ 294-90-6 ]
  • [ 99616-36-1 ]
  • [ 913972-22-2 ]
YieldReaction ConditionsOperation in experiment
88% With potassium carbonate In acetonitrile at 80℃; for 18h; 4.2.1. Compound 2 Cyclen (59 mg, 0.34 mmol) was dissolved in CH3CN (10 ml), K2CO3 (458 mg, 3.31 mmol) was added and the suspension was stirred for 15 min. Bromide 1 (465 mg, 1.65 mmol) in CH3CN (10 ml) was added dropwise and the mixture was heated at 80 °C for 18 h. After cooling the solid material was removed by filtration, the solvent was evaporated and the residue purified by column chromatography (CH2Cl2/CH3OH 92:8) to yield 290 mg (88%) of 2. Analytical data match to those previously reported for this molecule.
61% With potassium carbonate In acetonitrile at 65℃; for 24h; Inert atmosphere;
  • 46
  • [ 3792-04-9 ]
  • [ 294-90-6 ]
  • [ 1269772-31-7 ]
  • 47
  • [ 3792-04-9 ]
  • [ 294-90-6 ]
  • [ 1269772-29-3 ]
  • 48
  • [ 100-44-7 ]
  • [ 294-90-6 ]
  • [ 18084-64-5 ]
YieldReaction ConditionsOperation in experiment
75% With potassium carbonate In acetonitrile for 10.5h; Heating;
  • 49
  • [ CAS Unavailable ]
  • [ 294-90-6 ]
  • [ 18084-64-5 ]
YieldReaction ConditionsOperation in experiment
75% With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 72h; Inert atmosphere;
  • 50
  • [ 1400866-15-0 ]
  • [ 294-90-6 ]
  • [ 1400866-16-1 ]
YieldReaction ConditionsOperation in experiment
47.1% With triethylamine In chloroform for 23h; Inert atmosphere; Reflux;
  • 51
  • [ 57280-22-5 ]
  • [ 3926-62-3 ]
  • [ 294-90-6 ]
  • 10-(2,3-dihydroxy-1-hydroxymethylpropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate gadolinium [ No CAS ]
YieldReaction ConditionsOperation in experiment
160 kg of cyclen (1 ,4,7, 10-tetraazacyclododecane), 154 kg of 4,4-dimethyl-3,5,8- trioxabicyclo[5,1 ,0]octane and 34.7 kg of lithium chloride are initially charged in 325 kg of isopropanol and heated under reflux for 1320 minutes.1250 I of water are added, and the mixture is distilled until an internal temperature of 78C is reached. The mixture is then made up with 805 I of water, and 375 kg of sodium monochloroacetate are added at 35C, followed by 120 kg of 50% strength aqueous sodium hydroxide solution. The mixture is heated to an internal temperature of 65C, and a further 85 kg of 50% strength aqueous sodium hydroxide solution are added. If the pH drops below 12, it is re-adjusted with 10 kg of 50% strength aqueous sodium hydroxide solution (step-wise). The mixture is stirred at an internaltemperature of 65C for 90 minutes. After cooling to 50C, 240 kg of 36% aqueous hydrochloric acid are added such that the pH is now 3.1 - 4.9 (if appropriate, additional hydrochloric acid has to be added; it is important that the target pH is reached). At a jacket temperature of 95C and under reduced pressure, solvent (isopropanol/water mixture) is then distilled off to a total amount of 1200 kg.At 40C, 2554 kg of methanol are added and the pH is adjusted to 1.4 or less (1 .1 - 1 .3, optimum 1 .2) using 282 kg of 36% aqueous hydrochloric acid. The mixture is stirred at 40C for 35 minutes. The mixture is then cooled to 20C and theprecipitated sodium chloride (NaCI) is separated off using a centrifuge or a pressure nutsche filter (the filter cake is washed with methanol since the product is in solution). 996 (this is still being examined) I of water are added, and the methanol issubstantially distilled off at a jacket temperature of 90C (250 mbar), with water, the mixture is concentrated to a mass of 966 kg, and a further 1200 I of water are then added. 155 kg of gadolinium oxide are added to this solution, and the mixture is heated at 95C for 120 minutes. The mixture is allowed to cool to 50C and adjusted to pH 7.1 - 7.4 using lithium hydroxide monohydrate (this requires about 85 kg of lithium hydroxide monohydrate). At a jacket temperature of 120C and under reduced pressure, 895 kg of water are then distilled off. The mixture is allowed to cool to 73C, 5286 kg of alcohol (MEK = methyl ethyl ketone denaturized) are added and the water content is checked using the Karl-Fischer method. The water content is adjusted to 8.5%. (If the value is less than 7.0, an appropriately calculated amount of water is added. If the value is greater than 9.5%, an appropriate amount of ethanol is added. For the process, it is important that the value is in the range from 7.0 to 9.5). The mixture is then heated under reflux (78C) for 60 minutes. Eventually,spontaneous crystallization occurs. The mixture is stirred at a jacket temperature of 100C for 480 minutes and then allowed to cool to 20C.The product is isolated using a centrifuge or pressure nutsche, the filter cake twice being washed with ethanol. In a paddle drier, the crude product is dried at a jacket temperature of 58C for 90 minutes under reduced pressure (until a pressure of < 62 mbar and a temperature of > 46C are reached) or washed with ethanol three times and dried at < 34C. The product is then dried at an internal temperature of 48C for 60 minutes. The crude product is cooled to 20C and filled into containers. This gives 540 kg of a colourless crystalline powder (yield > 96%).
  • 52
  • [ 50465-95-7 ]
  • [ 294-90-6 ]
  • [ 1643807-50-4 ]
YieldReaction ConditionsOperation in experiment
95% In chloroform at 0℃; for 0.5h; Inert atmosphere;
  • 53
  • [ 4876-10-2 ]
  • [ 294-90-6 ]
  • 4-((1,4,7,10-tetraazacyclododecan-1-yl)methyl)quinoline-2(1H)-one [ No CAS ]
  • 54
  • [ 4876-10-2 ]
  • [ 294-90-6 ]
  • [Zn(4-((1,4,7,10-tetraazacyclododecan-1-yl)methyl)quinoline-2(1H)-one)]Cl2 [ No CAS ]
  • 55
  • [ 69658-97-5 ]
  • [ 294-90-6 ]
  • [ 1678518-18-7 ]
YieldReaction ConditionsOperation in experiment
38% With N-ethyl-N,N-diisopropylamine In acetonitrile at 65℃; for 6h; 3 Synthesis of 1 ,4-tetrakis(pyrazol-3 -methyl)- 1,4,7,1 0-tetraazacyclododecane (TPC) To a solution of Cyclen (1 g) in dry acetonitrile was added four equivalents of 3-(chloromethyl)pyrazole hydrochloride and eight equivalents of diisopropylethylamine. The mixture was stirred at 65 °C for 6 hours. The solvent was removed by rotary evaporation. The crude product was purified by column chromatography using basic alumina. Methanol (1% to 12%) in dichloromethane was used as an eluent. Fractions with pure product were combined, solvent removed in vacuo giving 38% yield.
  • 56
  • [ 220040-48-2 ]
  • [ 294-90-6 ]
  • [ 1821685-38-4 ]
YieldReaction ConditionsOperation in experiment
70% With potassium carbonate In acetonitrile at 80℃; for 12h; Schlenk technique; Inert atmosphere; 1 General procedure for H4tpaen derivatives (6a-e). Coupling step (5a-e) General procedure: Methyl 6-chloromethyl-pyridine-2-carboxylate 3 (500 mg, 2.7 mmol), K2CO3 (391 mg, 2.8 mmol) followed by freshly distilled acetonitrile (10 mL) were added to a Schlenk flask under argon atmosphere. Diamine (0.67 mmol) was then added. The mixture was stirred at 80 °C for 12 h. Acetonitrile was then removed under vacuum. The obtained residue was diluted with dichloromethane and washed with water. The organic layers were dried on Na2SO4, filtered and concentrated under vacuum. The resulting residue was recrystallized in i-PrOH.
  • 57
  • [ 4377-33-7 ]
  • [ 294-90-6 ]
  • [ 185130-32-9 ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate In acetonitrile Reflux; Lpy (Scheme 1, far left) was synthesized by a known procedure involving reaction of slightly greater than four equivalents of 2-picolylchloride with cyclen in the presence of excess Cs2CO3 (20 equivalents) in refluxing CH3CN. Lpyd, Lpyr, and Lpz, were synthesized in moderate yields using the corresponding chloromethyl N-heterocycles shown in Scheme 1. The chloromethyl N-heterocycles were synthesized by reacting the corresponding methyl N-heterocycles with equiv of trichloroisocyanuric acid in refluxing chloroform (see: Schiess et al., Org. Lett. 2011, 13, 1436, incorporated by reference). The chloromethyl N-heterocycles were purified by column chromatography prior to reactions with cyclen.
  • 58
  • [ 100-39-0 ]
  • [ 294-90-6 ]
  • [ 18084-64-5 ]
YieldReaction ConditionsOperation in experiment
89% With sodium hydroxide In water; acetonitrile for 6h; General synthetic procedure A: N-tetraalkylation of macrocycles General procedure: Macrocycle (1.0 equiv) and alkyl halide (4.1 equiv) were dissolved in a 1:1 mixture of aqueous 1 MNaOH and CH3CN (5-20 mL). The reaction mixture was shaken for 6 h. The resulting precipitate was collected by filtration, washed with hexane, and dried in vacuo to give the desired N-tetraalkyl derivative.
  • 59
  • [ CAS Unavailable ]
  • [ 294-90-6 ]
  • [ 60239-18-1 ]
YieldReaction ConditionsOperation in experiment
92.1% In acetonitrile for 6h; Inert atmosphere; Reflux; 10.4 Step (4): Preparation of compound 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) of formula 7 Keeping a slight positive pressure of nitrogen, 3L of acetonitrile and 149.02g (0.865mol) of the compound of formula 5 were added to the 5L reaction flask, and 477.57g (4.1mol) of sodium chloroacetate was added to it in batches with stirring. After the addition, the temperature was raised to reflux for reaction. The reaction was maintained under reflux for 6 hours, and the reaction was completed. The reaction solution was cooled to room temperature, filtered, and the filtrate was rotary evaporated to recover the solvent. The residue was recrystallized with an appropriate amount of toluene-acetonitrile (2:1, v/v) to obtain 323.32 g (0.797 mol) of white solid product. The yield is 92.1%, the total yield of the four-step reaction is 79.7%, Product titration purity: 99.7% (by HClO4),
With sodium hydroxide In lithium hydroxide monohydrate for 5h; Large scale; 2 Example 2: Larj.’e-scale Synthesis of DOTA A 6000 L reactor was charged with water (360 L) followed by cyclen (Kinsy, Spain; 180 kg, 1.O4Skrnol).A solution of sodium chloroacetate (Akzo Nobel, 540 kg, 4.55 kmol) in water (900 L) was added over a period of 1.5 hours, together with sodium hydroxide solution (377 kg50% w/w concentration; 4.71 kmol NaOH;) being added continuously to maintain the reaction pH at around pH 11. After the addition was complete, the reaction mixture was stirred for a further 5 hours.Concentrated hydrochloric acid (35%; ca. 462 kg) was added until the pH of the mixture was about pH 3.2. Then methanol was added (2340 L) at ca. 55 °C and cooled to 10 °C, cooling rate ca. 5 °C per hour.The precipitated crude DOTA was filtered off, and washed with aqueous methanol (1:2 vollvol; 4 x 315 L). The resulting cake was dried in the filter using reduced pressure and heating (55 °C jacket temperature).The above crude DOTA was dissolved in water and sampled for measurement of quantity and sodium content (369 kg DOTA; 87 % yield; 5.26 % Na) and subjected tonanofiltration whereby the sodium content was reduced from 5.26 w% to 0.84 w%. The aqueous solution this reduced salt DOTA was concentrated and then methanol added to induce crystallization and remove the remaining sodium chloride. The isolated crystals had a sodium content NMT 10 ig/g DOTA.
With lithium hydroxyde monohydrate; lithium hydroxide monohydrate at 0 - 30℃; for 24h; Embodiment 31 Cyclen (17.27 g, 100 mmol), lithium hydroxide monohydrate (36.92 g, 880 mmol) and water (80 mL) were added into a three-necked flask (1000 mL) at 0-10° C. A solution of sodium chloroacetate (51.25 g, 440 mmol) in water (30 mL) was added at 5-15° C. The mixture was warmed to 20-30° C. and reacted for 24 hours. No surplus of the raw material cyclen was detected by TLC. 36% hydrochloric acid (44.6 g, 440 mmol) and ethanol (600 mL) were added to the system for solids precipitation, followed by filtration. The resulting solids were purified by recrystallization with ethanol/water (volume ratio 3:1) and dried at 60° C. to obtain DOTA. Yield: 85.0%, HPLC: 89%, residue on ignition: 12.5%, moisture: 7.23%
  • 60
  • [ 884-74-2 ]
  • [ 294-90-6 ]
  • [ 2222986-64-1 ]
YieldReaction ConditionsOperation in experiment
60% In melt at 140℃; 1,4,7,10-tetrakis[(diphenylphosphoryl)methyl]-1,4,7,10-tetraazacyclododecane, DOTMPPh2. A mixture of cyclen (0.400g, 2.3mmol) and diphenylphosphorylmethanol Ph2P(O)CH2OH (2.160g, 9.3mmol) was melted and heated at 140°C for 4h. Water formed in the reaction was periodically removed under vacuum (1mmHg). The reaction mixture was cooled, dissolved in CHCl3 (10mL), applied to a silica gel column, and eluated with a mixture of CHCl3 and CH3OH (95/5 to 9/1). The main fracture was evaporated in vacuum to dryness, and the residue was treated with diethyl ether. The off-white precipitate was filtered off, washed with ether, and dried in air (1.485g, 60%). Mp 125-127°C. 1H NMR (200MHz, CDCl3): δ 2.47 (16H, s, NCH2), 3.24 (8H, d, 2JPH=4.26, NCH2P,), 7.32-7.48 (24H, m, Ar), 7.70-7.81 (16H, m, Ar). 13C{1H} NMR (50.04MHz, CD3CN): δ 134.7 (8C, d, 1JCP=93.9, 1-C, Ar), 132.7 (8C, d, 4JCP=2.3, 4-C, Ar), 131.9 (16C, d, 2JCP=8.8, 2-C, Ar), 129.7 (16C, d, 3JCP=11.1, 3-C, Ar), 56.1 (4C, d, 1JCP=83.6, NCH2P), 54.5 (8C, d, 3JCP=6.1, NCH2CH2NCH2P). 31P{1H} NMR (81.0MHz, CDCl3): δ 28.98 (1P, s). Anal. Calcd for C60H64N4O4P4·2H2O: C, 67.67; H, 6.39; N, 5.26. Found: C, 67.23; H, 7.02; N, 5.53.
  • 61
  • [ 946-99-6 ]
  • [ 294-90-6 ]
  • 1,4,7,10-tetrazazcyclododecane-N,N′,N′′,N′′′-tetramethylenecinnamic acid hydrochloride [ No CAS ]
  • 62
  • [ 57280-22-5 ]
  • [ 294-90-6 ]
  • 3 -(1,4,7,10-tetraazacyclododecan-1-yl)butane-1,2,4-triol tetrahydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
100 g of cyclones (1,4,7,10-tetraazacyclododecane) Dissolve in 500ml of purified water and warm to 40-45 C84 g of 4,4-dimethyl-3,5,8-trioxabicyclo [5,1,0] octaneAdd slowly React for 24 hours, add 408 ml of hydrochloric acid dropwise and stir at 75 C. for 2 hours. The reaction solution was concentrated in vacuo, 500 ml of ethanol was added thereto, stirred at reflux, and the resulting crystals were filtered.
  • 63
  • [ 57280-22-5 ]
  • [ 294-90-6 ]
  • [ 138147-50-9 ]
YieldReaction ConditionsOperation in experiment
With lithium chloride; In isopropyl alcohol; at 25 - 85℃; 92. Og of 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane (5) was added to a reaction mixture of lOOg of l,4,7,l0-tetraazacyclododecane (6) in 200mL of isopropyl alcohol at 25-30 C. To this solution 25 g of lithium chloride was added and heated to 80-85 C for 23-24hrs. On completion of reaction, the reaction mass was distilled off completely under vacuum. 500mL water was added to the crude and stirred. The pH of the reaction mixture was adjusted to 7-10.0 by adding 57.0 mL of acetic acid. The reaction mixture was diluted with 900 mL of dichloromethane and stirred at 25- 30 C. The phases were separated, the aqueous layer was treated with 50% sodium hydroxide and stirred for l0-l5mins. The reaction mixture was diluted with 600mL of the dichloromethane and phases were separated. The organic layer was dried over sodium sulphate, filtered and the filtrate so obtained was distilled off under vacuum to obtain solid 2,2-dimethyl-6-(l,4,7,l0-tetraazacyclododecan-l-yl)-l,3-dioxepan- 5-ol of formula (4). Yield: 78%; Purity: 86.96%.
  • 64
  • [ 67056-04-6 ]
  • [ 294-90-6 ]
  • [ 832079-71-7 ]
YieldReaction ConditionsOperation in experiment
61% With triethylamine In acetonitrile at 65℃; for 48h; Inert atmosphere; 2.2. Synthesis General procedure: N-n-butyl bromoacetamide and N-benzyl bromoacetamide were prepared by previously published methods [32,33]. DOTAM n-butyl and DOTAM-benzyl were synthesized according to Scheme1. Under a nitrogen atmosphere at room temperature, triethylamine (5.06 g, 50 mmol) was added to a solution of 1,4,7,10-tetraazacyclododecane (1.03 g, 6 mmol) and bromoacetamide (24 mmol) in 100 mL CH3CN (for DOTAM-n-butyl) or THF (for DOTAM-benzyl). The reaction mixture was stirred at 65 °C for 2 days. After cooling, the white solid was filtered and washed with cold CH3CN and ice-cold water, then dried under vacuum and recrystallized from CH3CN to afford the title compound as a colorless solid. DOTAM-n-butyl. (2.30 g, 61%) mp: 161-162 °C. FTIR (KBr, ν/cm-1): 3464, 3294(NH), 3236 (NH), 3080, 2958, 2933, 2870, 2823, 1659(C=O), 1554, 1456, 1306, 1238, 1101, 715. 1H NMR (400 MHz, CD3OD, ppm): δ 3.21 (t, 8H, CH2CH2NH), 3.08 (s, 8H, NCH2CO), 2.73(s, 16H, ring NCH2CH2N), 1.57-1.44 (m, 8H, CH3CH2CH2), 1.43-1.29 (m, 8H, CH3CH2CH2), 0.95 (t, 12H, CH3CH2). 13C NMR (100 MHz,CD3OD, ppm): δ 173.7 (CO), 59.9 (NCH2CO), 54.9 (ring NCH2CH2N), 40.2 (CH2CH2NH), 33.0 (CH3CH2CH2), 21.4 (CH3CH2CH2), 14.3(CH3CH2CH2). ESI-MS (m/z): Found: 625.5083 ([M+H]+), 647.4899([M+Na]+). Calcd: 625.5123 ([M+H]+), 647.4943 ([M+Na]+).
  • 65
  • [ 28446-58-4 ]
  • [ 294-90-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
93% In methanol for 24h; Reflux; 4.1. L1 Acrylamide (8.9 g, 100 mmol) and cyclen (4.31 g, 25 mmol) were dissolved in 125 mL methanol. The solution was heated under reflux for 24 h. The methanol was removed under reduced pressure and the residue stirred with Et2O to give a white paste. The Et2O was then decanted and methanol added. After stirring for a few minutes, the product was filtered on a Buchner funnel, washed with ethanol (4 10 mL), then Et2O. The product was dried in vacuo at 50 C overnight to give 3.9 as awhite solid. Yield: 9.0 g (93%). m.p. 170-172 C. Rf = 0.57. 1H-NMR (300 MHz, D2O, ): 2.29 (6H,t, 3J = 6.7 Hz, NCH2CH2CONH2), 2.42 (4H, br s, ring CH2), 2.55 (12H, br s, ring CH2), 2.62 (6H,t, 3J = 6.8 Hz, NCH2CH2CONH2); 13C-NMR (75 MHz, D2O, ); 32.36 (CH2CONH2), 45.15 (CH2),50.01 (CH2), 50.42 (CH2), 50.59 (CH2), 51.16 (CH2), 51.33 (CH2), 178.62 (C = O), 179.11 (C = O).Anal. Calcd (found) for C17H35N7O3*1.0H2O*0.4 C2H5OH: C, 50.7 (50.5); H, 9.4 (9.1); N, 23.3 (23.5).IR (max/(cm-1), KBr): 3349 (NH), 3154 (NH), 2969 (CH), 2837, 1673 (C = O), 1424.HRMS (+ES): found [M + H] + 386.2878. C17H36N7O3 requires 386.2874.
  • 66
  • [ 79-08-3 ]
  • [ 294-90-6 ]
  • [ 60239-18-1 ]
YieldReaction ConditionsOperation in experiment
87.8% With lithium hydroxide monohydrate; water at 0 - 30℃; for 24h; Embodiment 19 Cyclen (17.27 g, 100 mmol), lithium hydroxide monohydrate (36.92 g, 880 mmol) and water (80 mL) were added into a three-necked flask (1000 mL) at 0-10° C. A solution of bromoacetic acid (61.14 g, 440 mmol) in water (30 mL) was added at 5-15° C. The mixture was warmed to 20-30° C. and reacted for 24 hours. No surplus of the raw material cyclen was detected by TLC. 36% hydrochloric acid (44.6 g, 440 mmol) and ethanol (600 mL) were added to the system for solids precipitation, followed by filtration. The resulting solids were purified by recrystallization with ethanol/water (volume ratio 15:1) and dried at 60° C. to obtain DOTA. Yield: 87.8%, HPLC: 99.0%, residue on ignition: 0.119%, moisture: 7.90%
84.5% With lithium hydroxide monohydrate In water at 0 - 30℃; for 24h; 2 At 0-10 °C, 1,4,7,10-tetraazacyclododecane (17.27 g, 100 mmol), lithium hydroxide monohydrate (36.92 g, 880 mmol), and water (80 ml) were added to a three-necked flask (1000 ml). At 5-15 °C, a solution of bromoacetic acid (61.14 g, 440 mmol) in water (30 ml) was added. The mixture was heated to 20-30 °C and reacted for 24 h. TLC analysis showed no residue of the starting material, 1,4,7,10-tetraazacyclododecane. 36% hydrochloric acid (44.6 g, 440 mmol) and ethanol (600 ml) were added to the system, causing a solid to precipitate. The solid was filtered, and the resulting solid was purified by recrystallization from an ethanol/water mixture (3:1, v/v). The solid was dried at 60 °C to obtain DOTA with a yield of 84.5%, HPLC purity of 98.79%, single impurities >0.4%, and total impurities = 1.21%.
  • 67
  • [ 64-69-7 ]
  • [ 294-90-6 ]
  • [ 60239-18-1 ]
YieldReaction ConditionsOperation in experiment
72% With lithium hydroxide monohydrate; water at 0 - 30℃; for 24h; Embodiment 5 Cyclen (17.27 g, 100 mmol), lithium hydroxide monohydrate (36.92 g, 880 mmol) and water (80 mL) were added into a three-necked flask (1000 mL) at 0-10° C. A solution of iodoacetic acid (81.82 g, 440 mmol) in water (30 mL) was added at 5-15° C. The mixture was warmed to 20-30° C. and reacted for 24 hours. No surplus of the raw material cyclen was detected by TLC. 36% hydrochloric acid (44.6 g, 440 mmol) and ethanol (600 mL) were added to the system for solids precipitation, followed by filtration. The resulting solids were purified by recrystallization with ethanol/water (volume ratio 3:1) and dried at 60° C. to obtain DOTA. Yield: 72.0%, HPLC: 99.7%, residue on ignition: 0.02%, moisture: 6.20%
  • 68
  • [ 142342-55-0 ]
  • [ 294-90-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
47% With potassium carbonate In acetonitrile at 50℃; for 72h;
  • 69
  • [ 13497-18-2 ]
  • [ 109-70-6 ]
  • [ 294-90-6 ]
  • [ 2704550-81-0 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 1,3-chlorobromopropane; 1,4,7,10-tetraazacyclododecan With tert-butylmethyl ether; potassium carbonate In cyclohexane at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine With triethylamine In acetonitrile at 40℃; for 4h; Inert atmosphere; 1 Preparation Example 1 Put 8 mol (1105.68 g) of potassium carbonate into a 3L 4-necked round flask connected with a stirrer, thermometer, dropping funnel and shrink line, reduce the pressure to remove moisture completely, and then under an argon atmosphere. 4 mol (629.76 g) of 1-bromo-3-chloropropane, 1 mol (88.15 g) of t-butylmethyl ether, and 1 mol (84.16 g) of cyclohexane were added and stirred at 0° C. at 300 rpm. Here, 1 mol (172,27 g) of 1,4,7,10-tetraazacyclododecane (1,4,7,10-tetraazacyclododecane) was added over 1 hour through a dropping funnel, After completion of the input, the temperature was raised to room temperature to proceed with the reaction. Thereafter, 400 ml of cyclohexane was added, and after sufficient stirring, the remaining HBr was removed using a saturated aqueous sodium hydrogen carbonate solution. Thereafter, the salt was removed using distilled water and brine, and the remaining moisture was removed with sodium sulfate. Sodium sulfate was removed using a filter, the solvent was removed with a rotary concentrator, and then distilled to prepare a purified intermediate. Then, put the intermediate in a 5 L round-bottom flask connected to a shrink line and completely remove moisture under reduced pressure, and then put 1000 ml of acetonitrile under an irgon atmosphere, bis(3-triethoxysilyl)propylamine (bis(3-triethoxysilyl)propylamine) 4 mol (1702.2 g) and triethylamine (triethylamine) 10.12 g were added, heated to 40°C and stirred for 4 hours. Thereafter, the solvent and triethylamine were removed using a rotary concentrator to prepare a compound represented by the following Chemical Formula 1-1. It was confirmed that the prepared compound was synthesized by 1H-NMR (nuclear magnetic resonance spectroscopy).
  • 70
  • [ 294-90-6 ]
  • [ CAS Unavailable ]
  • [ 1235588-64-3 ]
YieldReaction ConditionsOperation in experiment
99% In water at 80℃; 4.4. General Procedure for Synthesis of Cu and Zn Complexes from Free Base Ligands General procedure: The free-base macrocycle cyclam or cyclen (1.0 equiv.) was dissolved in deionizedwater (10 mL). CuCl2 or ZnCl2 (1.0 equiv.) dissolved in deionized water (5 mL) was addedto the previous solution, and the reaction was heated to 80 C overnight. Thereafter, thesolvent was removed by evaporation under reduced pressure to quantitatively give thedesired complex.
87.9% In methanol at 68℃; for 24h; 4.7. Synthesis and characterization of four Zn(II) complexes General procedure: dded to high-temperature pressure pipes (15.0 mL) and the mixturewas reacted at 68 C for 24 h to yield the yellow products of Zn(BQTC)and Zn(TC), which were isolated and characterized (Schemes 1 3).Additionally, 1.0 mmol BQA or AP and H-Cur ligands with 1.0 equiv ofZnCl2, 3.5 mL of CH3OH, and 0.1 mL of KOH (0.1 M) were placed in 15-mL high-temperature pressure pipes. The mixture was heated at 65 Cfor 24 h to yield Zn(BQACur) and Zn(APCur) as the yellow products,which were isolated and characterized.
  • 71
  • [ 18084-64-5 ]
  • [ 294-90-6 ]
YieldReaction ConditionsOperation in experiment
90% With 10% Pd/C; hydrogen; benzyl chloride In water at 25 - 67℃; 1-3 Example 1: A preparation and purification method of cyclen, comprising the steps:(1) 26.6 g (0.21 mol) of benzyl chloride, 26.65 g (0.05 mol) of tetrabenzylcyclene and 2.67 g of 10wt% palladium-carbon catalyst were added to the hydrogenation reactor successively, then 30 g of deionized water was added, and the nitrogen was replaced by nitrogen. 6 times;(2) set the reaction temperature at 25°C, feed hydrogen into the hydrogenation reactor until the hydrogen pressure is 0.2MPa, stir to start the reaction, and the reaction pressure gradually decreases; heat up to 67 °C, the pressure rises first, then drops, continues to pass hydrogen, and keeps the reaction pressure at 0.4Mpa until the reaction is completed by sampling and detection;(3) material is cooled to 60 after the completion of the reaction, the reaction product is filtered under nitrogen protection, the palladium-carbon catalyst is recovered, and the filtrate is left to stand for stratification, the upper layer is a toluene layer, and the lower layer is an aqueous layer;(4) 10 g of sodium hydroxide was added to the obtained water layer, and the material was white and turbid; the temperature was raised to 95 ° C, the reaction was carried out until the material was clear, continued stirring for 1 h, cooled to 5 ° C for crystallization, and suction filtered to obtain a wet solid;(5) add toluene 26g to wet solid, be warming up to 100 of reflux dehydration;(6) Cool down to 30°C naturally, and stir for 1 minute every 30 minutes; after cooling to 30°C, a large amount of solids are precipitated; pass the cooling brine to 0°C, continue stirring, keep the temperature for 8h, filter and dry to obtain purified product 7.75g.
  • 72
  • [ 31106-82-8 ]
  • [ 294-90-6 ]
  • [ 185130-32-9 ]
YieldReaction ConditionsOperation in experiment
69% With potassium carbonate In acetonitrile at 25℃; for 48h;
  • 73
  • [ 24424-99-5 ]
  • [ 294-90-6 ]
  • [ 913542-69-5 ]
YieldReaction ConditionsOperation in experiment
58.3% With triethylamine In dichloromethane at 0℃; for 12h; Inert atmosphere; 1.S1 S1, preparation of intermediate IM1-1: Under nitrogen atmosphere, add cyclanine (20 g, 116.1 mmol) and dichloromethane (200 mL) to a 500 mL three-necked flask, and slowly cool to about 0°C; slowly drop di-tert-butyl dicarbonate (Boc)2O (50.7 g, 232 .2mmol); control the temperature at about 0 and stir the reaction for 12h; slowly add purified water (150mL) to quench, separate the liquids, extract the aqueous phase with dichloromethane (100mL*2), combine the organic phases, wash once with saturated brine (200mL), dry with anhydrous sodium sulfate, filter, concentrate the organic phase to dryness, separate by rapid column chromatography (silica gel), eluents are dichloromethane and methanol, and 32g of white solid intermediate IM1-1 is obtained (the nuclear magnetic spectrum is shown in Figure 7, the main product is the product of the above three Bocs, it is difficult to control the selection of reaction sites, resulting in the inability to carry out subsequent synthesis), the yield is 58.3%;
  • 74
  • [ 6959-47-3 ]
  • [ 294-90-6 ]
  • [ 185130-32-9 ]
YieldReaction ConditionsOperation in experiment
47% With caesium carbonate In acetonitrile at 82℃; for 24h; Inert atmosphere;
 

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