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Linagliptin intermediate, preparation method and applications thereof

A reaction and complete reaction technology, applied in the field of medicine, can solve problems such as difficulties in industrialized large-scale production, many impurities, and large energy consumption

Active Publication Date: 2015-09-09
SHENZHEN HAIBIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Based on the above methods, it can be seen that the existing linagliptin preparation method has a long route and poor safety; the raw materials are not easy to obtain, the yield is low, and the cost is high; the reaction temperature is high and energy consumption is large, resulting in many impurities and difficult separation Purification has brought difficulties to large-scale industrial production

Method used

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  • Linagliptin intermediate, preparation method and applications thereof
  • Linagliptin intermediate, preparation method and applications thereof
  • Linagliptin intermediate, preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0113] Synthesis of the compound shown in embodiment 1 formula (Ⅵ)

[0114]

[0115] Add 27g (0.2mol) of o-aminoacetophenone, 13.9g (0.2mol) of hydroxylamine hydrochloride, 240mL of absolute ethanol, and reflux at 80°C to monitor the reaction by HPLC; then Cool to 20°C, add 10% sodium hydroxide solution dropwise, adjust the pH of the reaction solution to 7.5, then cool the feed solution to 5°C, add an appropriate amount of water to make the reaction solution turbid, and let stand; then add about 400mL of water, grow crystals at 5°C for 30 minutes; filter with suction, wash with ethanol-water system, and dry in vacuo to obtain 24.84g of the compound shown in white solid formula (Ⅵ), with a molar yield of 82.8%, HPLC (%): 98.4% .

Embodiment 2

[0116] Synthesis of the compound shown in embodiment 2 formula (Ⅵ)

[0117]

[0118] Add 40.5g (0.3mol) of o-aminoacetophenone, 27.73g (0.399mol) of hydroxylamine hydrochloride, 360mL of anhydrous methanol, and reflux at 65°C to a 500mL four-necked flask with a thermometer, and monitor the reaction by HPLC; Then cool to 25°C, add 10% sodium carbonate solution dropwise, adjust the pH of the above liquid to 8.0, then cool the feed liquid to 15°C, add an appropriate amount of water to make the reaction liquid turbid, and let it stand; then add about 720mL dropwise water, grow crystals at 5-10° C. for 60 minutes; suction filtration, washing with methanol-water system, and vacuum drying to obtain about 37.04 g of the compound shown in white solid formula (Ⅵ), with a molar yield of 82.3%, HPLC (%): 98.1%.

Embodiment 3

[0119] Synthesis of the compound shown in embodiment 3 formula (Ⅵ)

[0120]

[0121] Add 13.5g (0.1mol) of o-aminoacetophenone, 13.9g (0.2mol) of hydroxylamine hydrochloride, 120mL of isopropanol, and reflux at 100°C to a 500mL four-necked flask with a thermometer, and monitor the reaction by HPLC; Then cool to 20°C, add 10% sodium hydroxide solution dropwise, adjust the pH of the reaction solution to 7.5, then cool the feed solution to 10°C, add an appropriate amount of water to make the reaction solution turbid, and let stand; then add About 260mL of water, then grow crystals at 5°C for 45 minutes; filter with suction, wash with isopropanol-water system, and dry in vacuo to obtain about 12.2g of the compound shown in white solid formula (Ⅵ), with a molar yield of 81.3%, HPLC ( %): 97.2%.

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Abstract

The present invention relates to a linagliptin intermediate, a preparation method and applications thereof, wherein the linagliptin intermediate has the structure represented by general formulas (II) and (IV), and X is halogen. According to the present invention, the compound of the present invention is the solid and has characteristics of low production cost, easy purification and easy storage, linagliptin can be efficiently prepared, and the method is suitable for industrial scale production.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a linagliptin intermediate and a preparation method and application thereof. Background technique [0002] Linagliptin, chemical name: 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, the structural formula is as follows: [0003] [0004] Linagliptin is an oral hypoglycemic drug developed by Boehringer Ingelheim Pharmaceutical Company of Germany, which was approved by the US FDA on May 2, 2011. Linagliptin mainly controls the blood sugar level of patients by inhibiting DPP-IV, and then is used in combination with exercise and diet to control the blood sugar level of patients with type Ⅱ diabetes. [0005] At present, the main synthetic routes of Linagliptin are: [0006] U.S. Patent No. 7,407,955 discloses that (A) is used as a substrate to react with (R)-3-tert-butoxycarbonylaminopiperidine to g...

Claims

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Application Information

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IPC IPC(8): C07D473/06
CPCC07D473/06
Inventor 唐天声李方灵卢兆强任鹏尚万里张验军
Owner SHENZHEN HAIBIN PHARMA
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