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New Trajenta crystal form and preparation method thereof

A technology of crystal form and ray powder diffraction, which is applied in the field of new crystal form of linagliptin, can solve problems such as inability to adapt to large-scale production, instability of crystal form A and B, etc., and achieve easy industrial preparation, good stability, crystal type stabilizing effect

Active Publication Date: 2016-01-27
QILU PHARMA HAINAN +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The pharmaceutical form of linagliptin reported in the existing literature is the crystalline form of linagliptin; among them, ① the linagliptin prepared by the compound patent WO2004 / 018468 is crystalline form A and crystalline Form B exists in the form of mixed crystals, and the temperature at which the two crystal forms convert to each other is 25±15°C, so the crystal forms A and B are unstable; Crystal form B, crystal form C, crystal form D, crystal form E and their preparation methods, crystal form C is heated to 30-100°C to obtain crystal form D, and crystal form C is obtained by drying at 70°C in the last step of the preparation process. The problem of crystal transformation; while crystal form E is prepared by melting crystal form D, which cannot be adapted to large-scale production

Method used

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  • New Trajenta crystal form and preparation method thereof
  • New Trajenta crystal form and preparation method thereof
  • New Trajenta crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1 Preparation of new crystal form of linagliptin

[0037]

[0038](1) 8-[(3R)-3-Boc-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-[( Add 6.1Kg of 4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione (compound II) into 62L of dichloromethane, then add 24.3kg of trifluoroacetic acid, and stir the reaction at room temperature 1.5h, add saturated sodium carbonate aqueous solution to adjust the pH value of the reaction solution to 6-8, separate the organic phase, evaporate the solvent under reduced pressure, and obtain an oil;

[0039] (2) Add 31.57L methanol to the oil obtained in step (1), heat to reflux to dissolve, add 1.33L purified water, keep stirring at 60°C until crystals precipitate, add 252L methyl tert-butyl ether, stir and cool down to 10-20°C ℃, filtered, and dried to obtain 3.85kg of white crystalline solid with a yield of 60.2%, HPLC purity of 99.94%, and moisture of 10.3%; after determination, its X-RPD spectrum is as follows: figu...

Embodiment 2

[0040] Embodiment 2 Preparation of new crystal form of linagliptin

[0041] 8-[(3R)-3-Boc-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-[(4-methyl Add 6 g of base-2-quinazolinyl)methyl]-1H-purine-2,6-dione into 48 mL of dichloromethane, add 18 g of trifluoroacetic acid, stir at room temperature for 1.5 h, add saturated aqueous sodium carbonate to adjust The pH value of the reaction solution was 6-8, the organic phase was separated, the solvent was distilled off under reduced pressure to obtain an oily substance; 90ml of ethanol was added, heated to reflux to dissolve, 6mL of purified water was added, and stirred at 55°C until crystals were precipitated, and 60ml of tertiary methyl Butyl ether was stirred and cooled to 25-30° C., filtered, and dried to obtain 3.45 g of white crystalline solid with a yield of 55.2%, a purity of 99.78%, and a water content of 10.1%. After determination, its X-RPD pattern and figure 1 Basically the same, its DSC-TGA spectrum and fi...

Embodiment 3

[0042] Embodiment 3 Preparation of new crystal form of linagliptin

[0043] 8-[(3R)-3-Boc-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-[(4-methyl Add 6 g of base-2-quinazolinyl)methyl]-1H-purine-2,6-dione into 90 mL of dichloromethane, add 30 g of trifluoroacetic acid, stir at room temperature for 1.5 h, add saturated aqueous sodium carbonate to adjust The pH value of the reaction solution is 6-8, separate the organic phase, distill off the solvent under reduced pressure to obtain an oil; add 90ml of methanol, heat to reflux to dissolve, add 3mL of purified water, keep stirring at 60°C until crystals are precipitated, add 240ml of isopropyl acetate The ester was stirred and cooled to 20-30° C., filtered, and dried to obtain 3.72 g of a white crystalline solid with a yield of 59.4%, a purity of 99.74%, and a water content of 10.2%. After determination, its X-RPD pattern and figure 1 Basically the same, its DSC-TGA spectrum and figure 2 Basically the same, its i...

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Abstract

The invention belongs to the technical field of pharmaceutical chemistry and particularly relates to a new Trajenta crystal form and a preparation method thereof. The crystal form has good chemical stability and crystal form purity and is easy to prepare on a large scale, operation is easy, and the crystal form can be better suitable for preparation of pharmaceutical preparations and large-scale production, and has a broad application prospect.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a new crystal form of linagliptin and a preparation method of the new crystal form. Background technique [0002] Linagliptin, chemical name: 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methanol Base-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione has a chemical structure as shown in formula I, developed by Boehringer Ingelheim and Approved by the FDA on May 2, 2011, it is used to improve the control of blood sugar levels in patients with type 2 diabetes in combination with diet and exercise. Linagliptin improves glycemic control in patients by inhibiting dipeptidyl peptidase-4 (DPP-4). Compared with other DPP-4 inhibitors, it has excellent renal safety and can effectively reduce the advantages of glycosylated hemoglobin. [0003] [0004] The pharmaceutical form of linagliptin reported in the existing literature is the crystal...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/04
CPCC07B2200/13C07D473/04
Inventor 冷传新王玉兵朱屹东鲍海忠刘培元范传文林栋
Owner QILU PHARMA HAINAN
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