Simple preparation method of high-purity linagliptin

A high-purity, simple technology, applied in the field of pharmaceuticals, can solve the problems of inability to control key intermediates, unsuitable for raw material drug declaration and production, etc., to achieve the effects of ensuring chiral purity, simplifying operations, and avoiding production

Active Publication Date: 2016-05-04
VALIANT CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] Moreover, in this invention, the key intermediates cannot be effectively con

Method used

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  • Simple preparation method of high-purity linagliptin
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  • Simple preparation method of high-purity linagliptin

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Experimental program
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Effect test

Embodiment 1

[0029] 60.0g (0.245mol) compound a (8-bromo-3-methylxanthine), 32.6g (0.245mol) compound b (1-bromo-2-butyne), 63.3g (0.490mol ) diisopropylethylamine and 570gN, N-dimethylformamide, warming up to 95-105 ℃, insulated and stirred for 4 hours, TLC monitoring without 8-bromo-3-methylxanthine residue (Rf (8-bromo -3-methylxanthine)=0.4, Rf (reaction solution)=0.6, developer: toluene / dehydrated alcohol=6 / 1, volume ratio), add 47.2g (0.245mol) compound d (2 -(chloromethyl)-4-methylquinazoline), continue to insulate and stir at 95-105°C for 3 hours, TLC monitors that there is no compound c(8-bromo-7-but-2-yn-1-yl-3 -Methyl-3,7-dihydro-1H-purine-2,6-dione) remaining (Rf (compound c) = 0.6, Rf (reaction solution) = 0.7, developer: toluene / absolute ethanol = 6 / 1, volume ratio), cooling the reaction solution to 5-25°C, slowly adding 600g of tap water dropwise to the system, stirring at 15-25°C for 0.5 hours, filtering, rinsing with toluene, and vacuum-drying the obtained solid at 70°C ...

Embodiment 2

[0034] 60.0g (0.245mol) compound a (8-bromo-3-methylxanthine), 32.6g (0.245mol) compound b (1-bromo-2-butyne), 63.3g (0.490mol ) diisopropylethylamine and 570gN, N-dimethylformamide, warming up to 90-100 ℃, insulated and stirred for 5 hours, TLC monitoring without 8-bromo-3-methylxanthine residue (Rf (8-bromo -3-methylxanthine)=0.4, Rf (reaction solution)=0.6, developer: toluene / dehydrated alcohol=6 / 1, volume ratio), add 47.2g (0.245mol) compound d (2-(chloro Methyl)-4-methylquinazoline), continue to stir at 90-100°C for 3 hours, TLC monitors that there is no compound c (8-bromo-7-but-2-yn-1-yl-3-methyl -3,7-dihydro-1H-purine-2,6-dione) remaining (Rf (compound c) = 0.6, Rf (reaction solution) = 0.7, developer: toluene / absolute ethanol = 6 / 1, volume ratio), the reaction solution was cooled to 5-25°C, and 600g of tap water was slowly added dropwise to the system, stirred at 15-25°C for 0.5 hours, filtered, rinsed with toluene, and the obtained solid was vacuum-dried at 70°C to ...

Embodiment 3

[0037]60.0g (0.245mol) compound a (8-bromo-3-methylxanthine), 32.6g (0.245mol) compound b (1-bromo-2-butyne), 49.5g (0.490mol ) triethylamine and 570gN-methylpyrrolidone, warming up to 90-100 ℃, insulated and stirred for 5 hours, TLC monitoring without 8-bromo-3-methylxanthine remaining (Rf (8-bromo-3-methylxanthine )=0.4, Rf (reaction solution)=0.6, developer: toluene / dehydrated alcohol=6 / 1, volume ratio), add 47.2g (0.245mol) compound d (2-(chloromethyl)-4-methyl Quinazoline), continue to stir at 90-100 ° C for 3 hours, TLC monitoring no compound c (8-bromo-7-but-2-yn-1-yl-3-methyl-3,7-dihydro -1H-purine-2,6-dione) remaining (Rf (compound c) = 0.6, Rf (reaction solution) = 0.7, developer: toluene / absolute ethanol = 6 / 1, volume ratio), the reaction solution Cool down to 5-25°C, slowly add 600g of tap water dropwise to the system, stir at 15-25°C for 0.5 hours, filter, rinse with toluene, and dry the obtained solid in vacuum at 70°C to obtain compound e (8-bromo-7-(2 -butyn-...

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Abstract

The invention relates to a simple preparation method of high-purity linagliptin. The method includes the steps of making 8-bromine-3-methyl xanthine and 1-bromo-2-butyne react, directly adding 2-chloromethyl-4-methylquinazoline without processing after reaction is completed, preparing a key intermediate 8-bromine-7-(2-butyne-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-diketone of linagliptin through a one-pot method, making the intermediate react with (R)-3-piperidinamine dihydrochloride after being filtered and separated to obtain a linagliptin solution, and obtaining a linagliptin pure product after processing the linagliptin solution. The key intermediate is prepared through the one-pot method, operation is convenient, and yield is increased; the key intermediate reacts with (R)-3-piperidinamine dihydrochloride after being separated, and therefore high-purity linagliptin is obtained, and the requirements for production and declaration of pharmaceutical enterprises are met to the maximum extent.

Description

technical field [0001] The invention relates to a simple preparation method of high-purity linagliptin, which belongs to the technical field of medicines. Background technique [0002] Linagliptin is a selective dipeptidyl peptidase Ⅳ (DPP-Ⅳ) inhibitor, which can significantly control blood sugar and has a good market prospect. Its structure is shown in the following formula (1): [0003] [0004] U.S. Patent No. 7,407,955 discloses: use (e) as a substrate to react with an amino compound protected by (R)-3-tert-butoxycarbonyl, and then use trifluoroacetic acid to remove the tert-butoxycarbonyl protecting group to obtain linagliptin. This route The reaction route is long, the consumption of trifluoroacetic acid is large, and the industrial production cost is high. [0005] Patent WO2013098775 discloses that (e) is used as a substrate to react with (R)-3-aminopiperidine, but the preparation process of the intermediate is too complicated, and the purity of the final produc...

Claims

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Application Information

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IPC IPC(8): C07D473/04
CPCC07B2200/07C07D473/04
Inventor 房立平李矩陈阳杜体建葛立权王志刚
Owner VALIANT CO LTD
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