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Linagliptin impurity, and preparation method and application thereof

A technology of impurities and uses, which is used as an impurity reference substance in the preparation method and quality control, in the field of linagliptin impurities, can solve problems affecting drug efficacy, side effects, etc., and achieve the effect of ensuring safety and effectiveness

Active Publication Date: 2016-04-20
BEIJING PUDEKANGLI PHARMA TECH DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The content of the active ingredient of a drug is an important indicator of the purity of the drug, and the impurities in the drug directly affect the efficacy of the drug and may cause toxic and side effects

Method used

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  • Linagliptin impurity, and preparation method and application thereof
  • Linagliptin impurity, and preparation method and application thereof
  • Linagliptin impurity, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] step one:

[0027]

[0028] Add N-methylpyrrolidone (1000ml) into the reaction kettle, add L409-1101 (166g, 0.18mol) and sodium carbonate (180g, 1.7mol) sequentially under stirring, and start adding L409-1102 (99.5g , 0.75mol) of N-methylpyrrolidone (375ml), and added dropwise within 1 hour, monitored by TLC, after the reaction was complete, L409-11 was obtained.

[0029] Step two:

[0030]

[0031] Heat the reaction solution in Step 1 to 100°C, add L409-2203 (144g, 0.75mol) into the reaction kettle, and wash the kettle wall with N-methylpyrrolidone (208ml); react at 115-120°C for 3-6h, monitor by HPLC, After the reaction was complete, post-treatment was performed to obtain 222 g of a yellow-brown solid (L409-22) with a yield of 72%.

[0032] Step three:

[0033]

[0034] Add the product obtained in Step 2 (222g, 0.48mol) into the reaction kettle, add N-methylpyrrolidone (666ml), stir slowly, raise the temperature to 115-120°C, and add N,N-diiso Propylethyl...

Embodiment 2

[0036] The impurity of formula (I) is used as a reference substance of related substances to determine related substances of linagliptin.

[0037] Chromatographic conditions: use octadecylsilane bonded silica gel as filler; use phosphate buffer as mobile phase A, use methanol-acetonitrile (55:45) as mobile phase B, and A-B (65:35) as mobile phase; The column temperature is 55°C; the detection wavelength is 225nm.

[0038] Need testing solution: take appropriate amount of this product, accurately weighed, add mobile phase A-acetonitrile (70:30) ultrasonically dissolve and quantitatively dilute to make a solution containing 0.5mg in every 1ml, as need testing solution.

[0039] Impurity reference substance solution: take an appropriate amount of linagliptin impurity shown in formula (I), accurately weighed, add mobile phase A-acetonitrile (70: 30) to dissolve and quantitatively dilute to make a solution containing 0.5 μg in every 1ml, as Impurity reference substance solution. ...

Embodiment 3

[0044] The impurity of formula (I) was used as a reference substance for related substances to determine related substances in linagliptin tablets.

[0045] Measure according to high performance liquid chromatography (Chinese Pharmacopoeia 2010 edition two appendix VD), chromatographic conditions refer to embodiment 2.

[0046] Need testing solution: take an appropriate amount of linagliptin tablet fine powder, accurately weighed, add mobile phase A-acetonitrile (70:30) to ultrasonically dissolve and quantitatively dilute to make a solution containing 0.5 mg per 1 ml, as the test product solution.

[0047]Impurity reference substance solution: take an appropriate amount of linagliptin impurity shown in formula (I), accurately weighed, add mobile phase A-acetonitrile (70: 30) to dissolve and quantitatively dilute to make a solution containing 0.5 μg in every 1ml, as Impurity reference substance solution.

[0048] Determination method: Precisely measure 10 μl each of the test ...

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Abstract

The invention discloses a linagliptin impurity as shown in a formula (I) which is described in the specification, a preparation method for the linagliptin impurity and application of the linagliptin impurity as an impurity reference substance for inspection of substance related to linagliptin. As the linagliptin impurity is applied as a standard reference substance, linagliptin quality can be effectively controlled, and security risks of a drug can be reduced, so security and validity of the linagliptin preparation in clinical application can be guaranteed.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a linagliptin impurity, a preparation method and use as an impurity reference substance in quality control. Background technique [0002] Linagliptin is a potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor developed by Boehringer Ingelheim, which can improve type 2 diabetes mellitus (T2DM) on the basis of diet control and physical exercise. ) level of glycemic control in adult patients. Compared with other gliptins, linagliptin has excellent renal safety. In May 2011, it was approved by the US FDA for marketing. Linagliptin chemical name: 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl-1)-3,7-dihydro-3-methyl- 1-[(4-methyl-2-quinazolinyl)methyl]-1H purine-2,6-dione, the chemical structure is: [0003] [0004] The content of the active ingredient of a drug is an important symbol reflecting the purity of the drug, and the impurities in the drug directly...

Claims

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Application Information

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IPC IPC(8): C07D473/04G01N30/88
CPCC07D473/04G01N30/88
Inventor 赵静赵拨刘福春
Owner BEIJING PUDEKANGLI PHARMA TECH DEV CO LTD
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