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Preparation of protected DO3A

A protected, ring-ringed vinening technology, applied in organic chemistry and other fields, can solve problems such as time-consuming, expensive, and unsuitable for large-scale production

Pending Publication Date: 2022-08-02
BRACCO IMAGINIG SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] The above methods typically require several days of reaction time followed by expensive and time-consuming purification of the crude product and are therefore not suitable for large-scale production

Method used

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  • Preparation of protected DO3A
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  • Preparation of protected DO3A

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0159] Example 1: Synthesis of DO3A-tri-tert-butyl ester monohydrobromide: work-up water 4x and wash water 2 (4x) (w / w) relative to starting cyclamenine

[0160] Synthesize according to the following synthetic scheme

[0161]

[0162] To commercial 1,4,7,10-tetraazacyclododecane (15.1 kg; 87.65 mol; concentration = 0.83 mol / LDMAC) and sodium acetate (22.65 kg; 276.11 mol) in DMAC (99 kg at 10°C) ; 105.3L) in the suspension was added tert-butyl bromoacetate (53.87kg; 276.11mol; concentration = 4.88mol / L DMAC) in DMAC (53.23kg; 56.63L) suspension, which lasted 2.5h. The temperature was then raised to 25°C and the mixture was stirred for 24h. Then water (60.0 kg; 4:1 w / w relative to the starting ring tengning) was added for 0.5 h. After 2 h, the mixture was centrifuged, and the collected cake was washed with water (2x60.0 Kg = 2x4:1 w / w, relative to the starting cyclamenine). The wet solid was dried in vacuo to yield 38,43 kg of the desired hydrobromide salt as a white powd...

Embodiment 2

[0167] Example 2: Synthesis of DO3A-tri-tert-butyl ester hydrobromide

[0168] Post-treatment water 4x and wash water 5.3x+4x (w / w) relative to the starting ring Tengning

[0169] The reactor was charged with cyclamenine (9 kg; 52.24 mol; 0.83 mol / L DMAC) and sodium acetate (13.5 kg; 164.57 mol) in DMAC (59.3 kg; 63.1 L). The obtained suspension was maintained at 25°C with stirring for 30 min. The suspension was then cooled at 10°C and a solution of tert-butyl bromoacetate (32.1 kg; 164.57 mol; 4.85 mol / L DMAC) in DMAC (31.9 kg; 33.9 L) was added over 3 h. The tubing was washed with DMAC (2.15 kg; 2.29 L), which was then added to the reaction mixture. The temperature was then raised to 25°C and the mixture was stirred for 24h. Water (36.1 kg; 4:1 w / w relative to the starting cyclamenine) was then added for 0.5 h and the mixture was centrifuged after 2 h and the cake was washed with water (47.4 kg + 36.5 kg). The wet solid was dried in vacuo to obtain 22.70 kg of the hydrob...

Embodiment 3

[0174] Example 3: Synthesis of DO3A-tri-tert-butyl ester hydrobromide

[0175] Post-treatment water 4x and wash water 2 (4x) (w / w) relative to the starting ring

[0176] The reactor was charged with cyclamenine (9 kg; 52.24 mol; 0.83 mol / L DMAC) and sodium acetate (13.5 kg; 164.57 mol) in DMAC (59.15 kg; 62.93 L). The obtained suspension was maintained at 25°C with stirring for 30 min. The suspension was then cooled at 10°C and a solution of tert-butyl bromoacetate (32.14 kg; 164.74 mol; 4.86 mol / L DMAC) in DMAC (31.85 kg; 33.88 L) was added over 3 h. The tubing was washed with DMAC (2.15 kg; 2.29 L), which was then added to the reaction mixture. The temperature was then raised to 25°C and the mixture was stirred for 24h. Water (36kg) was then added for 0.5h and after 2h the mixture was centrifuged and the cake washed with water (36.7kg+36.8kg). The wet solid was dried in vacuo to yield 24.16 kg of the hydrobromide salt.

[0177] Yield: 76.7%

[0178] Title HPLC: (for st...

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Abstract

The present invention relates to a process for the one-step preparation and isolation of protected DO3A, for example, DO3A-tri-tert-butyl esters as solid salts.

Description

[0001] Field of Invention [0002] The present invention relates to organic chemistry, in particular to the preparation of protected DO3A. More specifically, the present invention relates to a one-step preparation and isolation of protected DO3A such as DO3A-tri-tert-butyl ester (1,4,7,10-tetraazacyclododecane-1,4,7- tri-tert-butyl triacetate). [0003] Background of the Invention [0004] Magnetic resonance imaging (MRI) is a well-known diagnostic imaging technique that is increasingly used in clinical diagnosis for an increasing number of indications. [0005] The strong expansion of medical MRI has further benefited from the development of a class of compounds (MRI contrast agents) that act by causing significant changes in the relaxation rate of nearby water protons in the tissues / organs / fluids in which they are distributed, thereby linking relevant physiological The information adds to the impressive anatomical resolution typically obtained in non-contrast MRI images. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/02
CPCC07D257/02
Inventor A·菲尔里伽托S·加泽托
Owner BRACCO IMAGINIG SPA