Preparation method of linagliptin intermediate for treating type-II diabetes mellitus

An intermediate and system technology, which is applied in the field of preparation of linagliptin intermediates, can solve the problems of low product yield and difficult purification, and achieve the effects of simple operation, high yield and purity, and mild conditions

Active Publication Date: 2019-05-03
THE SECOND PEOPLES HOSPITAL OF SHENZHEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method obtains product yield low, and because isomer property is close, purification is difficult

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] A preparation method of linagliptin intermediate, comprising the following steps:

[0021] Under nitrogen protection, 100mmol of 8-bromo-3,7-dihydro-3-methyl-1H-purine-2,6-dione was dissolved in 200ml DMF, copper perchlorate (20mmol) and tetramethyl Add the DMF solution of ethylenediamine (20mmol), mix well, then add dropwise the DMF solution of 2-butyne (containing 2-butyne 150mmol), react at 50°C for 4 hours, then pour the reaction solution into water, dichloro Extracted with methane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, then recrystallized in a mixed solvent of petroleum ether and dichloromethane with a volume ratio of 20:1, filtered, and dried to obtain the 8-bromo bromide of Gliptin intermediate -3,7-Dihydro-3-methyl-9-(2-butynyl)-1H-purine-2,6-dione, yield 93.2%, purity 99.96% (HPLC area normalization method) .

Embodiment 2

[0023] A preparation method of linagliptin intermediate, comprising the following steps:

[0024] Under nitrogen protection, 100mmol of 8-bromo-3,7-dihydro-3-methyl-1H-purine-2,6-dione was dissolved in 200ml DMF, copper perchlorate (15mmol) and tetramethyl Add the DMF solution of ethylenediamine (15mmol), mix well, then add the DMF solution of 2-butyne (containing 200mmol of 2-butyne) dropwise, react at 50°C for 4 hours, then pour the reaction solution into water, dichloro Extracted with methane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, then recrystallized in a mixed solvent of petroleum ether and dichloromethane with a volume ratio of 20:1, filtered, and dried to obtain the 8-bromo bromide of Gliptin intermediate -3,7-dihydro-3-methyl-9-(2-butynyl)-1H-purine-2,6-dione, yield 93.5%, purity 99.93% (HPLC area normalization method) .

Embodiment 3

[0026] A preparation method of linagliptin intermediate, comprising the following steps:

[0027] Under nitrogen protection, 100mmol of 8-bromo-3,7-dihydro-3-methyl-1H-purine-2,6-dione was dissolved in 200ml DMF, copper perchlorate (20mmol) and tetramethyl Add the DMF solution of ethylenediamine (40mmol), mix well, then add dropwise the DMF solution of 2-butyne (containing 2-butyne 150mmol), react at 50°C for 4 hours, then pour the reaction solution into water, dichloro Extracted with methane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, then recrystallized in a mixed solvent of petroleum ether and dichloromethane with a volume ratio of 20:1, filtered, and dried to obtain the 8-bromo bromide of Gliptin intermediate -3,7-dihydro-3-methyl-9-(2-butynyl)-1H-purine-2,6-dione, yield 95.1%, purity 99.95% (HPLC area normalization method) .

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Abstract

The invention provides a preparation method of a linagliptin intermediate for treating type-II diabetes mellitus. According to the preparation method of the intermediate 8-bromo-3,7-dihydro-3-methyl-9-(2-butynyl)-1H-purine-2,6-dione, 8-bromo-3,7-dihydro-3-methyl-1H-purine-2,6-dione reacts with 2-butyne in an organic solvent in the presence of a copper catalyst and a cocatalyst to prepare the 8-bromo-3,7-dihydro-3-methyl-9-(2-butynyl)-1H-purine-2,6-dione. Operation is simple, conditions are mild, relatively high yield and purity are obtained, and the preparation method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method for a linagliptin intermediate, and belongs to the technical field of preparation of raw materials. technical background [0002] Linagliptin (English name is Linagliptin), chemical name is [(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl Base-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione, a dipeptidyl peptidase-4 (DPP-4) inhibitor , can improve blood sugar control in adult patients with type 2 diabetes mellitus (T2DM) on the basis of diet control and physical exercise. Compared with other gliptins, linagliptin has excellent renal safety. It does not require dose adjustment for patients with impaired renal function or the elderly over 75 years old, thus greatly expanding the scope of the drug population and improving the compliance of patients with medication. The U.S. Food and Drug Administration approved Linagliptin tablets on May 2, 2011. [0003] At present, there are many s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/06A61P3/10
Inventor 阎德文谭回左馨陈泽龙吴阳
Owner THE SECOND PEOPLES HOSPITAL OF SHENZHEN
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