Trelagliptin purification method

A purification method and mixed solvent technology, applied in organic chemistry and other directions, can solve the problems of low purity, low yield, solvates, etc., and achieve the effect of improving purification yield and high purity

Active Publication Date: 2015-08-12
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are some shortcomings in the crystal forms prepared by these solvents, either they are solvates, or the yield is not high, or the purity is not high

Method used

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Experimental program
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Effect test

Embodiment 1

[0018] Example 1 Preparation of Crude Trexagliptin

[0019] Add 93g of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile into a 10L three-necked flask , RAPD 60.3g, acetonitrile 372mL, lower the temperature below 10°C, and add DBU 212g dropwise. After the addition, the temperature was raised to 10-20°C, and the reaction was kept for 3 hours. Add ice water and dichloromethane, adjust pH=1-4 with 4M hydrochloric acid, separate liquid, wash water phase with DCM; combine water phase, add DCM, adjust pH=8-10 with saturated potassium carbonate solution, separate liquid, water phase Extract with DCM, combine the organic phases, dry, filter and concentrate to obtain 99 g of crude trexagliptin.

[0020] HPLC purity 98.0%.

Embodiment 2

[0021] The preparation of embodiment 2 Trexagliptin high-quality goods

[0022] Add 10 g of the crude trexagliptin of Example 1, 50 ml of isopropanol, and 10 ml of methyl acetate into the reaction flask, stir and heat to reflux, and slowly dissolve. After dissolving, remove the oil bath, lower the temperature to 0°C to 10°C, keep stirring for 1 hour, filter, and wash the filter cake with isopropanol. Dry in a vacuum oven at 45°C to constant weight to obtain 8.8 g of white solid

[0023] The yield is 88%, and the HPLC purity is 99.8%. The obtained solid is tested by X-powder diffraction, and the test results are shown in figure 1 .

Embodiment 3

[0024] The preparation of embodiment 3 Trexagliptin high-quality goods

[0025] Add 10 g of crude trexagliptin, 50 ml of isopropanol, and 10 ml of acetonitrile into the reaction flask, stir and heat to reflux, and dissolve slowly. After dissolving, remove the oil bath, lower the temperature to 0°C to 10°C, keep stirring for 1 hour, filter, and wash the filter cake with isopropanol. Dry in a vacuum oven at 45°C to constant weight to obtain 7.7 g of white solid

[0026] Yield 77%, HPLC purity 99.7%, the powder diffraction pattern of white solid and figure 1 Basically the same.

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Abstract

The invention relates to a trelagliptin purification method. The method comprises heating and dissolving trelagliptin in a mixed solvent, carrying out crystallization and separating solids, wherein the mixed solvent comprises isopropanol and one of methyl acetate, acetonitrile and ethanol. The trelagliptin purification method realizes a high trelagliptin yield and high trelagliptin purity.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for purifying trexagliptin. Background technique [0002] Trelagliptin is a dipeptidyl peptidase IV (DPP-4) inhibitor, its structural formula is as follows: [0003] [0004] Trexagliptin controls blood sugar levels by selectively and persistently inhibiting DPP-4. DPP-4 is an enzyme that triggers the inactivation of incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), two incretins in Plays an important role in blood sugar regulation. [0005] CN102675221A discloses a method for preparing trexagliptin. In the method, trexagliptin hydrochloride is dissolved in a mixed solvent of water and dichloromethane, and the pH>12 is adjusted with 50% sodium hydroxide solution. After methane extraction, the dichloromethane layers were combined and concentrated to dryness to give the free base as an off-whit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 但春燕左小勇张小成张上华张耀春雷皇书
Owner CHONGQING PHARMA RES INST
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