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Crystal form of gadotetrol compound and preparation method thereof

A compound, the technology of gadoteridol, which is applied in the crystal form of gadoteridol compound and its preparation field, can solve the problems affecting drug stability, application bioavailability and curative effect, appearance of different crystal forms, solubility, melting point, dissolution storage Stability differences and other issues, to achieve the effect of significant process purification, good stability, and meet the needs of drug production

Pending Publication Date: 2022-03-29
HAINAN PULIN PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When the same substance is crystallized, due to the influence of various factors, the intramolecular or intermolecular bonding mode changes, resulting in different arrangements of molecules or atoms in the lattice space and thus forming different crystal structures. Different crystal forms may have significant differences in appearance, solubility, melting point, dissolution rate, storage stability, etc., which will affect the stability, application, bioavailability and curative effect of the drug. Therefore, in order to obtain a superior physiochemical The specific crystal form of gadoteridol compound makes it beneficial to meet the needs of drug production, and a comprehensive investigation of the crystallization behavior of gadoteridol compound is required

Method used

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  • Crystal form of gadotetrol compound and preparation method thereof
  • Crystal form of gadotetrol compound and preparation method thereof
  • Crystal form of gadotetrol compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] The synthesis of embodiment 1 gadoteridol compound

[0063]

[0064] Synthesis of compounds of formula II

[0065] Add 9.37kg of N,N-dimethylacetamide, 1.00kg of compound of formula I, and 1.91kg of anhydrous sodium acetate into the reaction kettle, start stirring and cool down to -10-20°C, and dropwise add 4.53kg of tert-butyl bromoacetate , after the dropping, heat up to 25-35°C for heat preservation reaction. After the reaction is completed, add water to quench the reaction. After stirring, centrifugally filter, then rinse with water, put the wet product at 50-60°C and vacuum-dry to obtain 2.72kg of intermediate formula II Compound, yield 79.0%.

[0066] Synthesis of compounds of formula III

[0067] Add 24.00 kg of purified water and 3.00 kg of the compound of formula II to the reaction kettle in sequence, control the temperature at 15-25° C., add dropwise 3.6 L of 10% sodium hydroxide solution, and centrifugally filter after the reaction to obtain the compound...

Embodiment 2

[0072] Embodiment 2 Preparation of gadoteridol compound crystal form A

[0073] Add 1.00kg of crude gadoteridol compound, 0.9kg of purified water, and 0.79kg of isopropanol to the reaction kettle, heat up to 70-80°C and stir, then cool to 20-40°C to filter the reactant, and then rinse with isopropanol Wash the filter cake, put it into 30~40℃ and vacuum dry to get the crystal form A of the compound, the XRD pattern is as follows: figure 2 .

Embodiment 3-6

[0074] Example 3-6 Preparation of Gadoteridol Compound Form B

[0075] Take 100g gadoteridol compound crystal form A and place it under the humidity condition of 40-60%RH under the greenhouse for 24 hours, then add it to the mixed solution of 90g ether organic solvent and 83g ester organic solvent, Ultrasound at 50°C to dissolve it into a clear solution, filter it, place it at 5-10°C and stir to precipitate a solid, and then dry it in vacuum at room temperature to obtain crystal B. The XRD pattern is as follows: figure 1 , as shown in Table 4 below.

[0076] Table 4

[0077] Example ether organic solvent Ester organic solvent yield 3 methyl tert-butyl ether ethyl acetate 95％ 4 n-Propyl tert-butyl ether Butyl acetate 91％ 5 Anisole Isopropyl acetate 88％ 6 diphenyl ether ethyl benzoate 84％

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Abstract

The invention belongs to the field of chemical medicines, and particularly relates to a crystal form of a gadolinol compound and a preparation method thereof, and the compound can be used as a useful contrast agent in diagnostic medicine. The structural formula of the gadotetrol compound is shown as a formula VI, an X-ray powder diffraction pattern of the crystal form of the compound has characteristic peaks at the positions where 2theta diffraction angles are 8.58 degrees, 10.038 degrees and 10.962 degrees, and the error range of the 2theta value is + / -0.2 degrees; the novel preparation method of the gadadotetrol compound crystal form, provided by the invention, has a remarkable process purification effect and is suitable for large-scale industrial production; the crystal form provided by the invention has good stability and good reproducibility, is beneficial to the storage of raw material medicines and the development of preparations, and can effectively avoid the crystal transfer phenomenon in the development process of the preparations.

Description

technical field [0001] The invention relates to the field of chemistry and medicine, in particular to a crystal form of gadoteridol compound and a preparation method thereof, which can be used as a useful contrast agent in diagnostic medicine. Background technique [0002] Nuclear magnetic resonance imaging (Nuclear Magnetic Resonance Imaging, referred to as NMRI), also known as magnetic resonance imaging (MRI), has become a clinical medical diagnosis due to its non-invasive, high-resolution anatomical imaging, non-toxic and non-destructive to living bodies, etc. conventional diagnostic techniques. Magnetic resonance imaging is based on the relaxation of water protons in the human body from high-energy hydrogen nuclei to low-energy state nuclei under the condition of an external magnetic field. The image quality is affected by the density and distribution of water protons in the human body. Resonant image anatomy. The contrast agent can change the relaxation time of the su...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/02
CPCC07D257/02C07B2200/13
Inventor 朱逸凡范敏华王营辉吴族悌汪宇星龚亚红郭卫革陆翠军周胜军毛峙峙王可枫
Owner HAINAN PULIN PHARMA