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Linagliptin new crystal form and preparation method thereof

A technology of crystal form and crystal water, which is applied in the field of new crystal form of linagliptin and its preparation, can solve problems such as inability to adapt to large-scale production

Inactive Publication Date: 2017-08-15
ZHUHAI UNITED LAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Among them (1) US2007 / 0259900A1 discloses five crystalline forms of linagliptin A, B, C, D, and E and their preparation methods, and the company uses stable forms A and C as its pharmaceutical crystalline forms, wherein , Form B is converted from Form A at <10°C; Form D is transformed from Form C heated to 30°C-100°C, there is a problem of crystal form transformation, and Form E is formed by Crystal form D is obtained by melting and cannot be adapted to large-scale production

Method used

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  • Linagliptin new crystal form and preparation method thereof
  • Linagliptin new crystal form and preparation method thereof

Examples

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preparation example Construction

[0039] Preparation of amorphous crude product:

[0040] 20g 8-(3R)-amino-piperidin-1-yl-7-but-2-yne-3-methyl-1-((4-methylquinazolin-2-yl)-methyl) - Dissolve the solid xanthine in 100 mL of dichloromethane, fully stir to dissolve, and then concentrate to dryness to obtain 20 g of the amorphous form of Liagliptin, namely the crude amorphous product.

Embodiment 1

[0041] Embodiment 1: Preparation of linagliptin crystal form H

[0042] Take 5 g of the prepared amorphous crude product, add 10 mL of dimethyl sulfoxide, heat to 50 ° C to dissolve, take it out and cool to room temperature, add 10 mL of dioxane under slow stirring, and after solid is precipitated, lower the temperature by 0 to 5 ° C, Stirring was continued for 1 h. Filter and dry under vacuum at 45°C to obtain 3.2 g of off-white crystals. The yield is 64%, the HPLC purity is 98.78%, and the moisture is 0.3%. After determination, its XRD pattern and figure 1 Basically the same; its infrared spectrum and figure 2 Basically the same; the melting range measured by the melting point apparatus is: 150 ° C ~ 153 ° C; its DSC spectrum and image 3 Basically the same; its TGA spectrum is the same as Figure 4 Basically the same; observed under a microscope, the crystal form H is as Figure 5 shown.

Embodiment 2

[0043] Embodiment 2: Preparation of linagliptin crystal form H

[0044] Take 2 g of the prepared amorphous crude product, add 10 mL of dimethyl sulfoxide, heat to 40 ° C to dissolve, take it out and cool to room temperature, add 5 mL of dioxane under slow stirring, and cool down to 0 to 5 ° C after solids are precipitated. Stirring was continued for 1 h. Filter and dry under vacuum at 45°C to obtain 1 g of off-white crystals. The yield is 50%, the HPLC purity is 98.99%, and the moisture is 0.6%. After determination, its XRD pattern and figure 1 Basically the same; its infrared spectrum and figure 2 Basically the same; the melting range measured by the melting point apparatus is: 150 ° C ~ 153 ° C; its DSC spectrum and image 3Basically the same; its TGA spectrum is the same as Figure 4 Basically the same; observed under a microscope, the crystal form H is as Figure 5 shown.

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Abstract

The invention discloses a linagliptin new crystal form and a preparation method thereof, belonging to the technical field of medicinal chemistry. X-ray powder diffraction, infrared analysis, melting point measurement, differential scanning calorimetry, thermogravimetric analysis, and nuclear magnetic resonance are performed on the new crystal form. The linagliptin new crystal form is obviously different from the linagliptin crystal form in the prior art. The new crystal form has good chemical stability and crystal form purity, is easy to prepare in a large scale, is simple to operate, and has a broad application prospect.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a new crystal form of linagliptin and a preparation method thereof. Background technique [0002] Linagliptin, a dipeptidyl peptidase-4 inhibitor developed by Boehringer Ingelheim for the treatment of type 2 diabetes, was approved by the FDA in May 2011. [0003] The chemical name of linagliptin is 8-(3R)-amino-piperidin-1-yl-7-but-2-yne-3-methyl-1-((4-methylquinazolin-2-yl )-methyl)-xanthine, its structural formula is as shown in formula I: [0004] [0005] According to existing patent documents, linagliptin has amorphous and other crystalline forms, but linagliptin in crystalline form is used in medicine. Among them (1) US2007 / 0259900A1 discloses five crystalline forms of linagliptin A, B, C, D, and E and their preparation methods, and the company uses stable forms A and C as its pharmaceutical crystalline forms, wherein , Form B is converted from Form A at &...

Claims

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Application Information

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IPC IPC(8): C07D473/04
CPCC07D473/04C07B2200/13
Inventor 崔振华秦玉乔明福许华锋
Owner ZHUHAI UNITED LAB
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