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Linagliptin purification method

A purification method, an organic technology, applied in the direction of organic chemistry, etc., can solve the problem of high impurity content

Inactive Publication Date: 2016-06-29
ZHEJIANG JINGXIN PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In order to solve the problem of excessively high impurity content in the prior art, the present invention carries out post-treatment purification method on the crude product of linagliptin, which meets the requirements of ICH, and the impurity of isomer formula II can be effectively controlled at less than 0.1%.

Method used

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Experimental program
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Effect test

Embodiment 1

[0030] Preparation of crude linagliptin:

[0031] In a 500ml reaction flask, add 10g of intermediate IV (dissolved in 100ml of N,N-dimethylformamide), add 9.4g of potassium carbonate and 5.72g of aminopiperidine dihydrochloride, and heat the reaction to 90°C for reaction 6 hour, TLC monitors that the reaction ends, naturally cools to room temperature, adds 100ml of dichloromethane, removes potassium carbonate by filtration, and the filtrate is extracted with 100ml of water to separate liquids, and 100ml of dichloromethane is extracted twice again, the organic phases are combined, concentrated, and Liglie Tin crude product 8.2 g, HPCL=98.7%, isomer impurity formula II impurity HPLC=0.72%.

Embodiment 2

[0033] Preparation of crude linagliptin:

[0034]

[0035] In a 500ml reaction flask, add 4.53g of intermediate IV (dissolved in 50ml of N,N-dimethylformamide), add 2.76g of potassium carbonate and 2.0g of Boc-protected aminopiperidine, and heat the reaction to 80°C for 10 hours , TLC monitors the end of the reaction, naturally cools to room temperature, adds 100ml of dichloromethane, removes potassium carbonate by filtration, extracts the filtrate with 100ml of water, and extracts twice with 100l of dichloromethane, combines the organic phases, concentrates, and dissolves the crude product in 100ml of dichloromethane Add 3.52 grams of trifluoroacetic acid to methyl chloride, deprotect under stirring at room temperature, 5 hours, concentrate excess trifluoroacetic acid and solvent at room temperature, dissolve the crude product in 50 ml of dichloromethane, extract and separate the liquids with 50 ml of 10% sodium bicarbonate water Three times, the organic phase was concentr...

Embodiment 3

[0037] Purification of Linagliptin

[0038] 4.72 grams of linagliptin crude product (prepared in implementation one) was dissolved in 50 milliliters of 95% ethanol, and 2.0 grams of N-acetyl-L glutamic acid was added under reflux and dissolved in 20 milliliters of 95 percent ethanol solution. After adding, the temperature was naturally cooled to After stirring at room temperature for 2 hours, filter, wash with 10 ml of ethanol, and dry under reduced pressure at 50°C to obtain 6.35 grams of white linagliptin N-acetyl-L-glutamate, HPLC=99.83%, isomer impurity formula IIHPLC= 0.06%.

[0039] Put the above salt in 50 ml of dichloromethane, add 50 ml of 30% potassium carbonate aqueous solution, stir at room temperature for 2 hours, free and clear, separate liquid extraction, and concentrate the organic phase to obtain pure linagliptin free base. HPLC=99.86%, isomer impurity formula II HPLC=0.06%.

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Abstract

The invention provides a linagliptin purification method. The purification method comprises the following steps: mixing a coarse product of linagliptin and organic diacid in a solvent to carry out salt-forming reactions; separating salts generated through crystallization; and carrying out free alkali extraction and condensation to obtain purified linagliptin. The single purity content measured by HPLC is less than 0.1%.

Description

technical field [0001] The invention relates to a method for purifying a dipeptidyl peptidase-4 (DPP-IV) inhibitor, in particular to a method for purifying linagliptin. Background technique [0002] Linagliptin (Linagliptin) is an oral hypoglycemic drug developed by Boehringer Ingelheim Pharmaceutical Company of Germany. Chemical name: 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-[(4-methyl Base-2-quinazolinyl)methyl]-1H-purine-2,6-dione, the molecular structural formula is as follows: [0003] [0004] Linagliptin was approved for marketing by the US FDA on May 2, 2011, under the trade name Tradjenta. It mainly controls the blood sugar level of patients by inhibiting DPP-IV, and then is used to control the blood sugar level of patients with type 2 diabetes in combination with diet and exercise. [0005] PCT application WO2004018468 discloses the preparation method of linagliptin, the reaction formula is as follows: [0006] [0007] Patent a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/04
Inventor 徐苗焕黄悦
Owner ZHEJIANG JINGXIN PHARMA
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