A kind of purification method of linagliptin

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

Inactive Publication Date: 2017-11-03
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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  • A kind of purification method of linagliptin
  • A kind of purification method of linagliptin
  • A kind of purification method of linagliptin

Examples

Experimental program
Comparison scheme
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. After 6 hours, the TLC monitoring reaction was completed, cooled to room temperature naturally, added 100ml of dichloromethane, filtered to remove potassium carbonate, and the filtrate was extracted with 100ml of water to separate the liquids, extracted twice with 100ml of dichloromethane, combined the organic phases, concentrated, Delig Gliptin 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 In dichloromethane, add 3.52 g of trifluoroacetic acid, 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, and extract fractions with 50 ml of 10% sodium bicarbonate water liquid for three times, and the organic phase was concentrated to obtain 9.44...

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 g of white linagliptin N-acetyl-L-glutamate, HPLC=99.83%, isomer impurity formula II HPLC = 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 method for purifying linagliptin. The steps include salting the crude product of linagliptin and an organic diacid in a solvent, separating the salt produced by crystallization, and performing alkali free extraction and concentration to obtain purified linagliptin, whose single hetero 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 Patents(China)
IPC IPC(8): C07D473/04
Inventor 徐苗焕黄悦
Owner ZHEJIANG JINGXIN PHARMA
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