Preparation method of trelagliptin succinate

A technology of troxagliptin succinate and succinic acid, which is applied in the field of preparation of troxagliptin succinate, can solve the problems of difficulty in separating and purifying the final product, large amount of organic solvent, low yield and purity, and achieve convenient Solvent recovery, low toxicity, and short purification time

Inactive Publication Date: 2016-03-23
HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] The purpose of the present invention is exactly in order to overcome the deficiency of existing preparation method of succinate trexagliptin, provides a kind of novel preparation method of succinate trexagliptin, solves the difficulty of separating and

Method used

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  • Preparation method of trelagliptin succinate
  • Preparation method of trelagliptin succinate
  • Preparation method of trelagliptin succinate

Examples

Experimental program
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Effect test

Embodiment 1

[0062] Add 29.4g (0.1mol) of formula (2) and 17.3g (0.1mol) of (R)-3-amino-piperidine dihydrochloride into a 500mL three-necked flask, then add 46.6g (0.44mol) of sodium carbonate, 1.8mL of water and 260mL of ethanol were stirred and heated to 60°C, and kept at this temperature for 6 hours. Heating was stopped and 87 mL of acetonitrile was added, stirred and cooled to room temperature. After filtering, the filter cake was washed twice with 87 mL of acetonitrile respectively, the filtrate and washing liquid were combined, and rotary evaporated to dryness under reduced pressure at 45°C to obtain 40.3 g of crude product of formula (3) as light yellow solid.

[0063] The crude product of light yellow solid formula (3) is recrystallized, and the steps are as follows:

[0064] D1: First heat 241.8ml of ethanol to reflux, add 2.9g of activated carbon after the crude product of the light yellow solid formula (3) is completely dissolved, continue heating to reflux, and filter while it...

Embodiment 2

[0069] Add 29.4g (0.1mol) of formula (2) and 19.0g (0.11mol) of (R)-3-amino-piperidine dihydrochloride into a 500mL three-necked flask, then add 51.1g (0.37mol) of potassium carbonate, 1.9 mL of water and 260 mL of isopropanol were stirred and heated to 60°C, and kept at this temperature for 5 hours to react. Heating was stopped and 87 mL of acetonitrile was added, stirred and cooled to room temperature. Filter, wash the filter cake twice with 87mL acetonitrile respectively, combine the filtrate and washing liquid, and rotary evaporate to dryness under reduced pressure at 45°C to obtain 43.2g of the crude product of the light yellow solid formula (3); the crude product of the light yellow solid formula (3) Recrystallization, the steps are as follows:

[0070] D1: First heat 238ml of ethanol to reflux, add 3.1g of activated carbon after the crude product of the light yellow solid formula (3) is completely dissolved, continue heating to reflux, and filter while it is hot;

[0...

Embodiment 3

[0074] 1063g (3.62mol) of formula (2) and 689g (3.98mol) of (R)-3-amino-piperidine dihydrochloride were added to a 20L jacketed reactor, and then potassium carbonate 2200g (15.9mol), water 64mL and 9.4L of isopropanol were stirred and heated to 60°C, and kept at this temperature for 6 hours. Heating was stopped and 3.1 L of acetonitrile was added, stirred and cooled to room temperature. After filtering, the filter cake was washed twice with 3.1 L of acetonitrile respectively, the filtrate and washings were combined, and rotary evaporated to dryness at 35°C under reduced pressure.

[0075] 6.3 L of absolute ethanol was directly added to the crude product of the obtained light yellow solid formula (3) for recrystallization, and the recrystallization method was the same as in Example 2 to obtain 1173 g of white crystals of ethanol solvate of formula (3), with a total yield of 89.4%.

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Abstract

The invention relates to the technical field of drug preparation, and discloses a preparation method of trelagliptin succinate. The preparation method comprises the following steps: performing a reaction on a compound represented by a formula (2), (R)-3-amino-piperidine dihydrochloride and a weak base in a molar ratio of 1: (1-2): (1.5-5) to obtain a coarse product represented by a formula (3); and then recrystallizing the coarse product represented by the formula (3) by using an organic solvent with medium polarity to remove main impurities close to the coarse product represented by the formula (3) in polarity. The preparation method solves the problems in an existing preparation method that the difficulty for separating and purifying a final product is great, the yield and purity are low, the amount of the organic solvent during separation and purification is large and green industrial scaled production is not facilitated. The preparation method disclosed by the invention is high in total yield, and the purity of trelagliptin succinate is 99.83%, so that safe medication of trelagliptin succinate is guaranteed, and the quality and safe medication of trelagliptin succinate are improved.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a preparation method of trexagliptin succinate. Background technique [0002] Trelagliptinsuccinate, CAS number: 1029877-94-8, Chinese common name: 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4 -Dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile, a once-weekly dipeptidyl peptidase IV developed by Takeda (DPP-4) inhibitors control 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 the Plays an important role in blood sugar regulation. Inhibition of DPP-4 can increase blood glucose level-dependent insulin secretion, thereby controlling blood glucose levels. [0003] Trexagliptin succinate tablets were launched in Japan on March 7, 2015, under the trade name Zafatek. [...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 刘宣淦赵琛郑鹛吕裕斌
Owner HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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