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Preparation method of linagliptin dimer impurity

A technology for linagliptin dimer and impurities, which is applied in the field of preparation of linagliptin dimer impurities, can solve the problems that the preparation method of linagliptin impurity I is not reported in literature and the like, and achieves a short synthetic method route. , The effect of high reaction yield and high product purity

Pending Publication Date: 2022-01-25
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] There is no bibliographical report for the preparation method of this linagliptin impurity I at present

Method used

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  • Preparation method of linagliptin dimer impurity
  • Preparation method of linagliptin dimer impurity
  • Preparation method of linagliptin dimer impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Compound II, linagliptin (94.51g, 0.2mol) was added into dichloromethane and ethanol (400ml, V 二氯甲烷 :V 乙醇 =10:1) in a mixed solvent of 10:1) and stir to dissolve, add dimethyl azobisisobutyrate (4.61g, 0.02mol) and hydrochloric acid (110ml, 2.0mol / L) successively, heat to 35°C for about 10h, reduce Concentrate under pressure until cloudy, lower the temperature to 15-20°C, add methyl tert-butyl ether (200ml), continue to stir for 1h, filter, rinse the filter cake with cold ethanol (100ml, 0-5°C), and vacuum-dry at 45°C 12h, Liagliptin dimer impurity I was obtained, the yield was 97.12%, and the HPLC purity was 99.91%.

Embodiment 2

[0039] Compound II, linagliptin (94.51g, 0.2mol) was added into dichloromethane and tetrahydrofuran (400ml, V 二氯甲烷 : V 四氢呋喃 = 10:1) in a mixed solvent, stirring and dissolving, adding dimethyl azobisisobutyrate (3.68g, 0.016mol) and formic acid (220ml, 1mol / L) successively, heating to 30°C for about 10h, and depressurizing Concentrate until cloudy, cool down to 15-20°C, add methyl tert-butyl ether (200ml), continue to stir for 1h, filter, rinse the filter cake with cold ethanol (100ml, 0-5°C), and vacuum-dry at 45°C for 12h , the yield of Liagliptin dimer impurity I was 93.40%, and the HPLC purity was 99.82%.

Embodiment 3

[0041] Compound II, linagliptin (94.51g, 0.2mol) was added into dichloromethane and acetonitrile (400ml, V 二氯甲烷 :V 乙腈 =10:1) in the mixed solvent of stirring and dissolving, add dimethyl azobisisobutyrate (23.03g, 0.1mol) and acetic acid (110ml, 2mol / L) successively, heat to 50°C for about 10h, depressurize Concentrate until cloudy, cool down to 15-20°C, add methyl tert-butyl ether (200ml), continue to stir for 1h, filter, rinse the filter cake with cold ethanol (100ml, 0-5°C), and vacuum-dry at 45°C for 12h , the yield of Liagliptin dimer impurity I was 89.85%, and the HPLC purity was 99.31%.

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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a linagliptin dimer impurity. According to the invention, a linagliptin crude product is taken as a raw material, and the dimer impurity compound I is obtained from linagliptin under the action of an azo catalyst and acid. The method provided by the invention is simple, and the linagliptin impurity compound I obtained by the method is high in purity and high in yield, and can be used as an impurity reference substance in a linagliptin finished product detection standard.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of linagliptin dimer impurities. Background technique [0002] Linagliptin, the chemical name is 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl -1-[(4-Methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione; Molecular formula: C 25 h 28 N 8 o 2 ; Molecular weight: 472.54; CAS registration number: 668270-12-0, the structural formula is as follows: [0003] [0004] Linagliptin is an oral hypoglycemic drug developed by the Boehringer Ingelheim Pharmaceutical Company in Germany. It is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor and was approved by the US FDA on May 2, 2011. Listed under the trade name Tradjenta, in April 2013, Linagliptin was approved by the China Food and Drug Administration (CFDA) to be marketed in China. Clinical results have shown that this type of drug has a good hypoglycemic effect and has a...

Claims

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Application Information

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IPC IPC(8): C07D519/00G01N1/28G01N30/06
CPCC07D519/00G01N1/28G01N30/06G01N2001/2893
Inventor 王本利黄文波刘忠
Owner LUNAN PHARMA GROUP CORPORATION
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