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Preparation method of 1,4,7,10-tetraazacyclododecane-1,4,7-10-tetraacetic acid

一种酸性、烷基的技术，应用在有机化学等方向，能够解决耗能耗时长、不易操作、温度要求较高等问题

Active Publication Date: 2018-07-10
SHANGHAI VIWIT PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The technical problem to be solved by the present invention is to overcome the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) preparation process in the prior art or the existing Dealing with activated ionic resin, the need to concentrate and remove water in the later stage, and the long energy consumption during the concentration process, or the problem of high temperature requirements and difficult operation, or the need to use non-universal technologies such as nanofiltration technology etc., and provide a preparation method suitable for large-scale industrial production of DOTA, the whole process does not need to be purified by ion exchange resin and cryogenic refrigeration, and the product yield and purity are high

Method used

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  • Preparation method of 1,4,7,10-tetraazacyclododecane-1,4,7-10-tetraacetic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] At 0-10°C, add cyclen (17.27g, 100mmol), lithium hydroxide monohydrate (36.92g, 880mmol), and water (80mL) into a three-necked flask (1000mL). A solution of bromoacetic acid (61.14 g, 440 mmol) in water (30 mL) was added at 5-15 °C. Heat to 20-30° C. for 24 hours, and TLC detects that there is no remaining cyclen of the raw material. Add 36% hydrochloric acid (44.6g, 440mmol) to the system, add ethanol (600mL), precipitate a solid, filter, recrystallize and purify the obtained solid with ethanol / water (volume ratio: 3:1), and dry at 60°C to obtain DOTA.

[0065] Yield: 85.5%, HPLC: 99.7%, residue on ignition: 0.05%, moisture: 7.80%.

Embodiment 2

[0067] At 0-10°C, add cyclen (17.27g, 100mmol), lithium hydroxide monohydrate (36.92g, 880mmol), and water (80mL) into a three-necked flask (1000mL). A solution of bromoacetic acid (61.14 g, 440 mmol) in water (30 mL) was added at 5-15 °C. Incubate at 5-15°C for 24 hours, and TLC detects that there is no remaining cyclen of raw materials. Add 36% hydrochloric acid (44.6g, 440mmol) to the system, add ethanol (600mL), precipitate a solid, filter, recrystallize and purify the obtained solid with ethanol / water (volume ratio: 3:1), and dry at 60°C to obtain DOTA.

[0068] Yield: 78.0%, HPLC: 99.9%, residue on ignition: 0.05%, moisture: 6.25%.

[0069] Wherein, the HPLC purity data of product sees the table below (see figure 1 ), its retention time is 9.447min.

[0070] Table 1

[0071]

[0072]

Embodiment 3

[0074] At 0-10°C, add cyclen (17.27g, 100mmol), lithium hydroxide monohydrate (36.92g, 880mmol), and water (80mL) into a three-necked flask (1000mL). A solution of bromoacetic acid (61.14 g, 440 mmol) in water (30 mL) was added at 5-15 °C. Heat to 35-45° C. for 24 hours, and TLC detects that there is no remaining cyclen of the raw material. Add 36% hydrochloric acid (44.6g, 440mmol) to the system, add ethanol (600mL), precipitate a solid, filter, recrystallize and purify the obtained solid with ethanol / water (volume ratio: 3:1), and dry at 60°C to obtain DOTA.

[0075] Yield: 82.3%, HPLC: 99.6%, residue on ignition: 0.06%, moisture: 5.60%.

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Abstract

The invention discloses a preparation method of 1,4,7,10-tetraazacyclododecane-1,4,7-10-tetraacetic acid (DOTA). The preparation method includes the steps of in water phase, subjecting 1,4,7,10-tetraazacyclododecane (cyclen) and XCH2COOR to alkylation reaction under the action of an acid-binding agent; adjusting pH to isolate crude DOTA; recrystallizing. The preparation method is suitable for large-scale industrial production of DOTA; the whole process has no need for purification by ion exchange resin and low-temperature freezing; the product yield s high; the product purity is 99.0% and above; single impurity content is < / =0.05%; residue on ignition is <0.10%; the preparation method meets the quality standard for bulk pharmaceutical chemicals.

Description

technical field [0001] The invention relates to a preparation method of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. Background technique [0002] 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), English name 1,4,7,10-tetraazacy-clododecane-1,4,7 ,10-tetraacetic acid, whose structure is shown in the following formula, is an important chemical intermediate. [0003] [0004] In 1976, Stetter Hermann and Wolfram Frank first reported the synthesis of DOTA (Angewandte Chemie International Edition in English 15(11):686), using 1,4,7,10-tetraazacyclododecane (cyclen) Reaction with chloroacetic acid in alkaline medium, and then purified by Dowex-2×8 ion exchange resin to remove inorganic salts to obtain qualified products. [0005] In 1980, J.F. Desreux used sodium hydroxide as alkali, the reaction temperature was 80°C, and then acidified to adjust the pH to 2.5 to obtain the product, and Dowex 50W-X4 ion exchange resin was used to purify DOTA (Ino...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/02
CPCC07D257/02
Inventor 孟周钧何一刚魏彦君邢艳平
Owner SHANGHAI VIWIT PHARMA CO LTD
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