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Simple preparation method of II-type antidiabetic drug linagliptin

A simple and simple technology for diabetes, which is applied in the field of diabetes, can solve the problems of complicated operation, too many raw materials, and long time consumption, and achieve the effect of cheap and easy-to-obtain raw materials, simple processing and operation, simple and easy operation

Inactive Publication Date: 2015-08-19
WUHAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route is complicated to operate, takes a long time, and requires too many raw materials, so this method needs to be improved

Method used

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  • Simple preparation method of II-type antidiabetic drug linagliptin
  • Simple preparation method of II-type antidiabetic drug linagliptin
  • Simple preparation method of II-type antidiabetic drug linagliptin

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 3-Methyl-7-(2-butyn-1-yl)-8-bromo-xanthine (2.7 g, 9 mmol) was added to 2-chloromethyl-4-methylquinazoline (2.1 g, 10.8mmol) and potassium carbonate (1.9g, 13.5mmol) in DMSO (30ml) solution, under the catalysis of potassium iodide (0.015g, 0.09mmol), react at 70 ℃ for 7 hours, then add potassium carbonate (1.9g , 13.5mmol), while adding (R)-3-aminopiperidine (1.1g, 10.8mmol), reacted at 70°C for 8 hours with a one-pot method, and added twice the amount of saturated saline ( 60ml), the solid was precipitated, and the crude product (4.1g) was obtained by suction filtration. The crude product was recrystallized with methanol (4.5ml), filtered by suction, and dried to obtain the pure product 8-[(3R)-3-aminopiperidine-1 - Base] -7-(2-butynyl)-3,7-dihydro-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-1H-purine- 2,6-Diketone (3.8 g).

[0038] The infrared absorption spectrogram (IR spectrum testing instrument: BrukerVECTOR-22, test condition: KBr tablet) of the product obtain...

Embodiment 2

[0043] 3-Methyl-7-(2-butyn-1-yl)-8-bromo-xanthine (8.1 g, 27 mmol) was added to 2-chloromethyl-4-methylquinazoline (6.3 g, 32.4mmol) and potassium carbonate (5.7g, 40.5mmol) in DMSO (90ml) solution, under the catalysis of potassium iodide (0.045g, 0.27mmol), react at 80 ℃ for 7 hours, then add potassium carbonate (5.7g , 40.5mmol), while adding (R)-3-aminopiperidine (3.3g, 32.4mmol), reacted at 80°C for 8 hours with a one-pot method, and added twice the amount of saturated saline ( 180ml), precipitated a solid, and filtered it with suction to obtain the crude product (12.4g). The crude product was recrystallized with methanol (13ml), filtered with suction, and dried to obtain the pure product 8-[(3R)-3-aminopiperidine-1- Base] -7-(2-butynyl)-3,7-dihydro-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-1H-purine-2 , 6-diketone (11.9 g).

Embodiment 3

[0045] 3-Methyl-7-(2-butyn-1-yl)-8-bromo-xanthine (81 g, 270 mmol) was added to 2-chloromethyl-4-methylquinazoline (63 g, 324 mmol) and potassium carbonate (57g, 405mmol) in DMSO (900ml) solution, under the catalysis of potassium iodide (0.45g, 2.7mmol), react at 70°C for 8 hours, then add potassium carbonate (57g, 405mmol), and add (R)-3-aminopiperidine (33g, 324mmol) was reacted at 70°C for 7 hours in a one-pot method, and two times the amount of saturated saline (1800ml) was added after the reaction was completed, and a solid was precipitated, filtered by suction, The crude product (121g) was obtained, and the crude product was recrystallized with methanol (125ml), filtered and dried to obtain the pure product 8-[(3R)-3-aminopiperidin-1-yl]-7-(2-butyne yl)-3,7-dihydro-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-1H-purine-2,6-dione (115 g).

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Abstract

The invention discloses a simple preparation method of II-type antidiabetic drug linagliptin which comprises the following steps: adding 3-methyl-7-(2-butyne-1-yl)-8-bromo-xanthine into a DMSO (dimethylsulfoxide) solution of 2-chloromethyl-4-methyl-quinazoline and potassium carbonate A, and under the catalysis of potassium iodide, reacting for 7-8 hours at a temperature of 70-80 DEG C; adding potassium carbonate B and (R)-3-aminopiperidine, and reacting for 7-8 hours at a temperature of 70-80 DEG C; after the reaction is completed, adding saturated salt water, separating out solids, and carrying out suction filtration to obtain a crude product linagliptin; and recrystallizing the crude product linagliptin with methyl alcohol, carrying out suction filtration and drying, thus obtaining a target product. The method disclosed by the invention is implemented by using a one-pot method, so that the method is simple and easy to operate and short in reaction steps, and raw materials are cheap and easily available, therefore, the method is applicable to industrial mass production; and the method overcomes the problems in the conventional method that impurities are difficult to remove, line operations are complicated and time-consuming, and too many raw materials are required.

Description

technical field [0001] The invention relates to the field of diabetes, in particular to a simple preparation method of linagliptin, a drug for type II diabetes. Background technique [0002] Diabetes mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia. Hyperglycemia is caused by defective insulin secretion or impaired biological action, or both. The long-term high blood sugar in diabetes leads to chronic damage and dysfunction of various tissues, especially the eyes, kidneys, heart, blood vessels, and nerves. [0003] About 25.8 million people in the United States currently suffer from type 1 or type 2 diabetes, and this number is as high as 220 million worldwide. Type Ⅱ diabetes is the most common type of diabetes, accounting for about 95% of all diabetes cases. Diabetes is a chronic disease caused by the body's inability to properly produce or use insulin. The main types of diabetes medications currently used are: [0004] (1) Sulfonylureas: ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/06A61P3/10
CPCC07D473/06
Inventor 秦华利郝建宏陈小清尚振鹏
Owner WUHAN UNIV OF TECH
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