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Preparation method for crystal form of linagliptin

A technology of crystal form and seed crystal, which is applied in the field of preparation of linagliptin crystal form, can solve the problems of difficult removal of impurities, increase of economic cost, pressure of waste liquid treatment, unreasonable use, etc.

Inactive Publication Date: 2018-05-11
JIANGSU ALICORN PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The crystal form has high purity and good drug potential. However, the inventor found in the research that the use of up to 40 times the amount of organic solvent increases the economic cost and the pressure of waste liquid treatment; the high temperature of 90 ° C makes the crystal form Impurities produced during the preparation process are difficult to remove; it is unreasonable to restrict the use of second-class solvents in the last step of drug preparation

Method used

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  • Preparation method for crystal form of linagliptin
  • Preparation method for crystal form of linagliptin

Examples

Experimental program
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Effect test

Embodiment 1

[0021] The 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4- Methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione crude product (purity of 98.66% by HPLC normalization) 10.00g, dissolved in 100ml ethanol, heated to 60~65℃ , Stir until completely dissolved. After stirring for 10 minutes, the temperature was lowered to an internal temperature of 40°C, and seed crystals were added to the clear liquid, and the system quickly became turbid. Continue to cool down to room temperature, stir at room temperature for 2 hours, then stir at 0~5°C for 1 hour, filter, and vacuum dry the filter cake at 50°C for 6 hours to obtain 8.69g of solid powder of the target crystal form (purity by HPLC normalization method: 99.53%) ).

Embodiment 2

[0023] The 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4- Methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione crude product (purity 98.66% by HPLC normalization) 5.00g, dissolved in 20ml methanol, heated to 45~50℃ , Stir until completely dissolved. After stirring for 10 minutes, the temperature was lowered to an internal temperature of 35°C, and seed crystals were added to the clear liquid, and the system became turbid quickly. Continue to cool down to room temperature, stir at room temperature for 2 hours, then stir at 0~5°C for 2 hours, filter, and dry the filter cake under vacuum at 50°C for 6 hours to obtain 3.08g of solid powder of the target crystal form (purity 99.62% by HPLC normalization method) ).

Embodiment 3

[0025] The 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4- Methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione crude product (purity 98.66% by HPLC normalization) 5.00g, dissolved in 75ml isopropanol, heated to 60~ 65°C, stir until completely dissolved. After stirring for 10 minutes, the temperature was lowered to an internal temperature of 45°C, seed crystals were added to the clear liquid, and the system became turbid quickly. Continue to cool down to room temperature, stir at room temperature for 2 hours, then stir at 0~5°C for 1 hour, filter, and vacuum dry the filter cake at 50°C for 6 hours to obtain 3.80g of solid powder of the target crystal form (purity 99.47% by HPLC normalization method) ).

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Abstract

The invention specifically relates to a preparation method for a crystal form of linagliptin, belonging to the field of medicine. The preparation method has the advantages of simple operation, good reproducibility, good purification effect, suitability for industrial production, etc.

Description

Technical field [0001] The invention belongs to the field of medicine, and specifically relates to a preparation method of linagliptin crystal form. Background technique [0002] Linagliptin (Linagliptin), the structure shown in formula I, the chemical name: 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)- 3,7-Dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione. [0003] [0004] Formula I [0005] Linagliptin was jointly developed and marketed by Boehringer Ingelheim and Eli Lilly. It is a DPP-4 inhibitor, mainly used to improve the control of blood glucose levels in adults with type 2 diabetes by combining diet and exercise. Drug treatment or combined with other anti-diabetic drugs. [0006] Linagliptin was approved to be listed in the United States, Japan and Europe in May, July and August 2011. The trade names are Tradjenta, Trajenta, Trazenta. In March 2013, CFDA approved Linagliptin for "combined use with metformin and sulfonylureas, in conjunction with d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/04
Inventor 陈磊陆平波刘玉先吴心宇高超
Owner JIANGSU ALICORN PHARMATECH CO LTD
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