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Industrial preparation process of linagliptin

A preparation process and reaction technology, applied in the field of industrialized preparation technology of linagliptin, can solve the problems of complicated operation, large amount of solvent, waste of energy and the like, and achieve the effect of simple operation and less amount of solvent

Inactive Publication Date: 2015-04-08
SHOUGUANG FUKANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the methods adopted in domestic and foreign patents and literatures are that the intermediates in each step are purified and then put into the next step, resulting in low product yield, complicated operation, large solvent consumption and waste of energy.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Example 1: 1.92kg (10mol) of reactant a (2-chloromethyl-4-methylquinazoline) and 2.97kg (10mol) of reactant b (8-bromo-7-(2 -butynyl)-3-methylxanthine), potassium carbonate 2.76kg (10mol), 10L dimethyl sulfoxide heated to 80°C and reacted for about 3 hours, TLC detected that the reaction was complete. Add reactant c ((R)-3-phthalimide piperidine tartaric acid) 2.3kg (10mol) directly to the mother liquor, N,N-diisopropylethylamine 2.02kg (20mol) and heat up to 85°C After 4 hours of reaction, the reaction was detected by TLC and the reaction was complete. The reaction mother liquid was not treated and directly added 2.4kg (40mol) of ethanolamine at 20-100°C for 2-10 hours. After the reaction was detected by TLC, purified water was added dropwise, and 4.5kg of crude linagliptin was obtained by suction filtration. The yield was 95.34%, and the content determined by HPLC was 95.33%. Add 22.5L of absolute ethanol and heat up to 75-79°C to dissolve the crude linagliptin, cool...

Embodiment 2

[0017] Embodiment two: 1.92kg (10mol) reactant a (2-chloromethyl-4-methylquinazoline), 2.97kg (10mol) reactant b (8-bromo-7-(2 -butynyl)-3-methylxanthine), potassium carbonate 2.76kg (10mol), 10L dimethyl sulfoxide heated to 90°C and reacted for about 2 hours, TLC detected that the reaction was complete. Add reactant c ((R)-3-phthalimide piperidine tartaric acid) 2.3kg (10mol) directly to the mother liquor, N,N-diisopropylethylamine 2.02kg (20mol) and heat up to 85°C After 4 hours of reaction, the reaction was detected by TLC and the reaction was complete. The reaction mother liquid was not treated and directly added 2.4kg (40mol) of ethanolamine at 20-100°C for 2-10 hours. After the reaction was detected by TLC, purified water was added dropwise, and 4.63kg of crude linagliptin was obtained by suction filtration. The yield was 98.09%, and the content determined by HPLC was 95.66%. Add 22.5L of absolute ethanol and heat up to 75-79°C to dissolve the crude linagliptin, cool do...

Embodiment 3

[0018] Example three: 1.92kg (10mol) of reactant a (2-chloromethyl-4-methylquinazoline) and 2.97kg (10mol) of reactant b (8-bromo-7-(2 -butynyl)-3-methylxanthine), cesium carbonate 3.25kg (10mol), 10L dimethyl sulfoxide heated to 90°C and reacted for about 2 hours, TLC detected that the reaction was complete. Add reactant c ((R)-3-phthalimide piperidine tartaric acid) 2.3kg (10mol) directly to the mother liquor, N,N-diisopropylethylamine 2.02kg (20mol) and heat up to 90°C After 3 hours of reaction, the reaction was detected by TLC and the reaction was complete. The reaction mother liquid was not treated and directly added 2.4kg (40mol) of ethanolamine at 20-100°C for 2-10 hours. After the reaction was detected by TLC, purified water was added dropwise, and 4.67kg of crude linagliptin was obtained by suction filtration. The yield was 98.94%, and the content measured by HPLC was 95.73%. Add 22.5L of absolute ethanol and heat up to 75-79°C to dissolve the crude linagliptin, cool...

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Abstract

The invention relates to the technical field of medicines and particularly relates to an industrial preparation process of linagliptin. The industrial preparation process comprises the steps of adding a reactant a (2-chloromethyl-4-methyl-quinazoline), an equal molar ratio of reactant b (8-bromo-7-(2-butynyl)-3-methylxanthine), an acid-binding agent and a proper amount of solvent into a reaction kettle to react at 0-140 DEG C for 3-8 hours, after TLC detection reaction is finished, directly adding a reactant c ((R)-3-phthalimide piperidine-tartaric acid) and an acid-binding agent, namely N,N-diisopropylethylamine without processing a reaction mother liquid to react at 0-125 DEG C for 3-10 hours, after the TLC detection reaction is finished, adding ethanolamine without processing the reaction mother liquid to react for 2-10 hours, after the TLC detection reaction is finished, dropwise adding purified water, carrying out suction filtration to obtain a linagliptin rough product, and refining by virtue of a refining method disclosed in a patent CN101437823A, so as to obtain a linagliptin refined product. According to the industrial preparation process, linagliptin is synthesized by virtue of a one-pot continuous feeding method, the consumption of the solvent is low, and the operation is easy; and the industrial preparation process is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to an industrial preparation process of linagliptin. Background technique [0002] Diabetes is a slowly progressive disease. It is estimated that there are currently about 240 million diabetic patients in the world, and its incidence is increasing rapidly. A considerable number of patients died from AIDS, and it has become the third most harmful disease to human health after tumors and cardiovascular diseases. More than 90% of diabetic patients are type 2 diabetes, so the current major antidiabetic drug research is carried out for type 2 diabetes. Type 2 diabetes mellitus is a metabolic disease with chronic hyperglycemia mainly due to insulin resistance with relative insulin insufficiency and defects in insulin secretion with or without insulin resistance. Traditional hypoglycemic agents mainly include insulin sensitizers, insulin secretagogues, and α-glucosidase inhibitors. Th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/04
CPCC07D473/04
Inventor 宋伟国李书涛夏艳田梅宋成刚高东圣董良军
Owner SHOUGUANG FUKANG PHARMA
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