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Synthesis of tris n-alkylated 1,4,7,10-tetraazacyclododecanes

A technology of tetraazacyclododecane, which is applied in the field of synthesis of tri-N-alkylated 1,4,7,10-tetraazacyclododecane, which can solve the problem of high labor costs and purification steps Trouble, time-consuming and other problems, to achieve the effect of effective response and easy operation

Active Publication Date: 2008-09-17
THE UNIVERSITY OF HONG KONG
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Problems solved by technology

But because of low yields and high labor costs, current methods of preparing tri-substituted cykrins are unsatisfactory, for example, in the recent work of Yoo, Reichert and Welch (Yoo et al., Chem. Comm., 2003, 766) In their work, tri-N-alkylated cyclines were prepared from cyclines through four different protection and deprotection steps, and the pH was adjusted during the alkylation process, Sammes and Parker reported in cyclines Tri-N-substituted Cyklin was prepared by direct alkylation between Lin and electrophile, but unfortunately because of low regioselectivity, its yield was around 20-40% (Bruce et al., J Am.Chem .Soc., 2000, 122, 9674, Dadabhoy et al., J Chem.Soc., Perkin Trans.22002, 348)
Known methods use an excess of sekrin during alkylation in order to obtain the monoalkylated product despite the consumption of the sekrin reactant, additionally the process includes protection, functionalization and deprotection steps, this multi-step routes are multidirectional and not always available, and purification steps are often cumbersome and time-consuming

Method used

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  • Synthesis of tris n-alkylated 1,4,7,10-tetraazacyclododecanes
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  • Synthesis of tris n-alkylated 1,4,7,10-tetraazacyclododecanes

Examples

Experimental program
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Embodiment 1

[0032] Example 1: Tris-(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (1)

[0033] Dissolve 3.3 equivalents of tert-butyl bromoacetate (773.0 mg, 7.6 mmol) in 10.0 mL of anhydrous chloroform, and add dropwise to 1,4,7,10-tetraazacyclododecane (Sikelin) ( 400.0 mg, 2.32 mmol) and 10.0 equivalents of triethylamine (2.3 g, 23.2 mmol) in a mixture of 40 mL of anhydrous chloroform, the reaction was carried out under an argon atmosphere for about half an hour, and the reaction mixture was stirred for 2 hours, and 0.5 equivalent anhydrous K 2 CO 3 , the solution obtained after 14 hours of reaction was washed with water (3×40 mL), washed with anhydrous Na 2 SO 4 The organic phase was dried and the solvent was removed under reduced pressure to give a clear oil. The crude product was purified by flash chromatography on alumina (dichloromethane / methane=200:5 (v / v), R f =0.35), to obtain tris-(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (1) as a white powder...

Embodiment 2

[0034] Example 2 Tris-[(diphenyl)methylcarbamoylmethyl]-1,4,7,10-tetraazacyclododecane (2)

[0035] Dissolve 3.3 equivalents of N-2-chloroacetyl-diphenylmethylamine (1.98 g, 7.6 mmol) in 10.0 mL of anhydrous chloroform and add dropwise to 1,4,7,10-tetraazacyclododecane (Sikelin) (400.0mg, 2.32mmol) and 10.0 equivalents of triethylamine (2.3g, 23.2mmol) in a mixture of 40mL of anhydrous chloroform, the reaction was carried out for about half an hour under an argon atmosphere, and then the reaction was stirred The mixture was stirred for 2 hours, and 0.5 equivalent of anhydrous K was added 2 CO 3 , the solution obtained after 15 hours of reaction was washed with water (3×40 mL), washed with anhydrous Na 2 SO 4 The organic phase was dried and the solvent was removed under reduced pressure to give a bright yellow solid. Purify by flash chromatography on alumina (dichloromethane / methane=200:10 (V / V), R f = 0.30) crude product, tris-[(diphenyl)methylcarbamoylmethyl]-1,4,7,10-...

Embodiment 3

[0036] Example 3 Tris-[(R)-1-(1-phenyl)ethylcarbamoylmethyl]-1,4,7,10-tetraazacyclododecane (3)

[0037] Dissolve 3.3 equivalents of (R)-N-2-chloroacetyl-1-phenylethylamine (1.51 g, 7.6 mmol) in 10.0 mL of anhydrous chloroform and add dropwise to 1,4,7,10 tetraaza In a mixture of cyclododecane (Secline) (400.0 mg, 2.32 mmol) and 10.0 equivalents of triethylamine (2.3 g, 23.2 mmol) in 40 mL of anhydrous chloroform, the reaction was carried out under an argon atmosphere for about half an hour , and the reaction mixture was stirred for another 2 hours, and 0.5 equivalent of anhydrous K was added 2 CO 3 , the solution obtained after 14 hours of reaction was washed with water (3×40 mL), washed with anhydrous Na 2 SO 4 The organic phase was dried and the solvent was removed under reduced pressure to give a white solid. The crude product was purified by flash chromatography on alumina (dichloromethane / methane=200:12 (V / V), R f =0.25), to obtain three-[(R)-1-(1-phenyl)ethylcarb...

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Abstract

A directly synthetic method for preparing tris-alkylated 1,4,7,10-tetraazacyclododecanes by the reactions of 1,4,7,10-tetraazacyclododecane (cyclen) and appropriate electrophiles is accomplished in high yield. The method provides operational convenience, starting material availability, cost economy, atom efficiency and reaction insensitivity to temperature, moisture, and concentrations of starting materials.

Description

background of the invention [0001] Magnetic Resonance Imaging (MRI) is an established and powerful method of studying the internal structures of the human body and is currently used by all major hospitals in the world. It can provide physicians with clear images of the inside of the human body from any angle without using harmful radiation. Compared with other diagnostic methods such as ultrasonography and computerized X-ray thermography (CT), MRI is a non-invasive method. The method can not only provide excellent three-dimensional images of living soft tissues, but also reveal the function and physiological state of the physiological processes of internal organs. [0002] The rapid expansion of medical MRI has prompted the development of contrast-enhancing agents (contrast agents) that are used to enhance the contrast between normal and diseased tissue and / or to improve diagnostic sensitivity and sensitivity by accelerating water proton relaxation in surrounding tissue. spec...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D257/02A61B5/05A61N5/02
CPCC07D257/02
Inventor 黄永德李聪
Owner THE UNIVERSITY OF HONG KONG
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