DOTA crystal form and preparation method thereof

A crystal form, ray powder diffraction technology, applied in II and III and their preparation, DOTA crystal form I field, can solve the problems such as failure to obtain DOTA crystal form, and achieve the effects of good solubility and simple preparation method

Pending Publication Date: 2021-07-09
VIWIT PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] However, none of the above DOTA preparation or p

Method used

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  • DOTA crystal form and preparation method thereof
  • DOTA crystal form and preparation method thereof
  • DOTA crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Embodiment 1: the preparation of DOTA pure product:

[0101] Step 1: At 0-10°C, add cyclen (172.7g, 1mol), lithium hydroxide monohydrate (369.2g, 8.8mol), and water (800mL) into a three-necked flask (1000mL). A solution of bromoacetic acid (611.4 g, 4.4 mol) in water (300 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 (446.0g, 4.4mol) to the system, add ethanol (6L), 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 Crude product 347.7g, yield 90%.

[0102] Step 2: Weigh 100.0g of the DOTA crude product obtained in step 1, add ultrapure water to a volume of 300mL, raise the temperature to 50°C, stir for 1h, add 900mL of ethanol dropwise, then cool down to 0-5°C and stir for 1h, filter and collect White solid, then add 300mL of ultrapure water to the white solid, raise the...

Embodiment 2

[0105] Weigh 10.0 g of DOTA pure product prepared as in Example 1, add 40 mL of ultrapure water, raise the temperature to 30-35 ° C, stir for 1 h, add dropwise 120 mL of ethanol, keep at 30-35 ° C, stir and crystallize for 1 h, filter, and collect white Solid, dried under vacuum at 50-55°C to obtain DOTA Form I.

[0106] Yield: 95.3%, HPLC purity: 99.98%, moisture: 7.28%.

Embodiment 3

[0108] Weigh 10.0g of DOTA pure product prepared as in Example 1, add 50mL of ultrapure water, raise the temperature to 30-35°C, stir for 1h, add dropwise 100mL of ethanol, keep at 30-35°C, stir and crystallize for 1h, filter and collect White solid, dried under vacuum at 50-55°C to obtain DOTA crystal form I.

[0109] Yield: 70.0%, HPLC purity: 99.93%.

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Abstract

The invention discloses DOTA crystal forms I, II and III and a preparation method thereof. The preparation method of the DOTA crystal form is simple, and the DOTA crystal form has better solubility, stability and low hygroscopicity, and has important value for optimizing and developing a subsequent synthesis process.

Description

technical field [0001] The present invention relates to DOTA crystal forms I, II and III and a preparation method thereof. Background technique [0002] Gadoteric acid NMR contrast agent is a widely used clinical injection. It is a complex formed by Gd(Ⅲ) and DOTA. It has the characteristics of good water solubility, low osmotic pressure and stable chemical properties. It can be widely used It is used in angiography, venography and gastrointestinal contrast, but high-purity DOTA must be used to prepare gadoteric acid. Therefore, it is very necessary to study the purification method of DOTA. During the purification process, it is found that different crystal forms of DOTA can be obtained under different conditions. [0003] Currently, literatures report DOTA preparation or purification methods that contain a crystallization step, mainly including: [0004] In 1991, Clarke and A.Martel (Inorganica Chimica Acta, 190, pp 27-36) concentrated the filtrate after desalting with io...

Claims

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Application Information

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IPC IPC(8): C07D257/02
CPCC07D257/02C07B2200/13
Inventor 孙亚洲拉杰斯·萨胡魏彦君孔猛黄长全邢艳平徐青景
Owner VIWIT PHARMA
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