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A kind of preparation method of linagliptin intermediate

A technology of intermediates and reaction time, which is applied in the field of preparation of linagliptin intermediates, can solve the problems of high reaction conditions and operation requirements, expensive starting materials, and low atom utilization, and achieve good industrialization prospects and product yields. High efficiency and purity, easy operation

Active Publication Date: 2020-09-25
安庆奇创药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Regarding the preparation process of linagliptin, although many methods have been reported, there are still problems such as high reaction conditions and operation requirements, expensive starting materials and low atom utilization, metal pollution and low yield.

Method used

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  • A kind of preparation method of linagliptin intermediate
  • A kind of preparation method of linagliptin intermediate
  • A kind of preparation method of linagliptin intermediate

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Experimental program
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Embodiment 1

[0038] Embodiment 1: the preparation of formula II compound

[0039]

[0040] 2-Bromo-4-methylimidazole (1.610g, 10mmol), N-methylurea (0.889g, 12mmol), tert-butyl hydroperoxide (70%, 2.574g, 20mmol), and 20mL of acetonitrile were added to In a 100mL flask, heat the reaction system to 70°C, stir and react for 8 hours, cool to room temperature after the reaction, add 80mL ethyl acetate to dilute the reaction solution, wash once with saturated aqueous sodium chloride solution, then wash twice with water, and spin off under reduced pressure. Ethyl acetate gave crude product. The crude product was recrystallized from dichloromethane and cyclohexane to obtain 2.372 g of compound II with a yield of 96% and a purity of 99%. 1 HNMR (300MHz, CDCl 3) δ 13.00 (s, 1H), 12.27 (s, 1H), 8.19 (s, 1H), 7.87 (s, 1H), 2.75 (s, 3H). Mass spectrum (ESI): m / z = 246.9828 (M+H).

Embodiment 2

[0041] Embodiment 2: the preparation of compound II

[0042] 2-Bromo-4-methylimidazole (1.610g, 10mmol), N-methylurea (0.889g, 12mmol), tert-butyl peroxide (70%, 2.574g, 20mmol), 20mL of acetonitrile were added accordingly Put it into a 100mL flask, heat the reaction system to 90°C, stir and react for 8h, cool to room temperature after the reaction, add 80mL ethyl acetate to dilute the reaction solution, wash once with saturated aqueous sodium chloride solution, then wash twice with water, and spin evaporate under reduced pressure Ethyl acetate was removed to give the crude product. The crude product was recrystallized from dichloromethane and cyclohexane to obtain 2.223 g of compound II with a yield of 90% and a purity of 99%.

Embodiment 3

[0043] Embodiment 3: the preparation of compound II

[0044] 2-bromo-4-methylimidazole (1.610g, 10mmol), N-methylurea (1.111g, 15mmol), tert-butyl hydroperoxide (70%, 2.574g, 20mmol), 20mL dioxane Put it into a 100mL flask accordingly, heat the reaction system to 100°C, stir and react for 10h, cool to room temperature after the reaction, add 80mL of ethyl acetate to dilute the reaction solution, wash once with saturated aqueous sodium chloride solution, then wash twice with water, reduce Ethyl acetate was distilled off under pressure to obtain a crude product. The crude product was recrystallized from dichloromethane and cyclohexane to obtain 1.976 g of compound II with a yield of 80% and a purity of 99%.

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Abstract

The invention provides a preparation method of a linagliptin intermediate. The preparation method comprises the following steps: (1) reacting 2-bromo-4-methylimidazole, N-methylurea and an oxidizing agent to obtain a compound II; (2) reacting the compound II with a bromine source in the presence of an alkali to obtain a compound III; and (3) reacting the compound III with 1-bromo-2-butyne in the presence of alkali to obtain a compound IV that is the key linagliptin intermediate. The method has the advantages of cheap and easily available initial raw materials, simplified steps, high atom utilization rate, mild reaction conditions, high yield, suitability for industrial production and the like.

Description

technical field [0001] The invention relates to a preparation method of a linagliptin intermediate, which belongs to the technical field of Yiyue chemical industry. Background technique [0002] The chemical name of linagliptin is 8-[(3R)-3aminopiperidin-1-yl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1 -[(4-Methylquinazolin-2-yl)methyl]-1H-purine-2,6-dione, jointly developed by Boehringer Ingelheim and Eli Lilly and Company, approved by the US FDA in May 2011 . The wood strain dipeptidyl peptidase IV (dipeptidylpeptidase-IV, DPP-1V) inhibitor is mainly used in combination with diet and physical exercise to control the blood sugar level of adult patients with type 2 diabetes. Its mechanism of action is to reduce the degradation of glucagon-like peptide-1 (GLP-1), increase the plasma concentration of GLP-1, and improve postprandial blood glucose control by inhibiting DPPIV, which is a new way to treat type 2 diabetes. The drug has definite curative effect, few adverse reactions, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/04
CPCC07D473/04
Inventor 杨博海威
Owner 安庆奇创药业有限公司