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Purification method of trelagliptin succinate

A technology of troxagliptin succinate and a purification method, which is applied in the field of medicinal chemistry, can solve the problems of affecting the efficacy of the product and low purity of the final product, and achieve the effects of simple operation and improved yield and purity

Inactive Publication Date: 2017-05-31
ZHENGZHOU MINGZE MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the preparation process of troxagliptin succinate currently reported, there are often isomers produced during the nucleophilic substitution reaction process, resulting in low purity of the final product and affecting the efficacy of the product. Therefore, the research and development of A purification method suitable for industrial production with high yield and high purity of trexagliptin succinate, which is of great significance to the research and development of drugs for the prevention and treatment of diabetes

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] The purification method of the present embodiment trexagliptin succinate comprises the following steps:

[0022] 1) Preparation of crude trexagliptin succinate: Take 560ml of THF and 80.6g of 2-({6-[(3R)-3-amino-1-piperidin-1-yl]-3 -Methyl-2,4-dioxo-3,4-dihydro-1(2H)-yl}methyl)-4-fluorobenzonitrile is added to the reaction flask, heated to 50°C until the added reactant is complete Dissolve, add 28.0g of succinic acid to react for 0.6h, then remove the heating device, cool down to room temperature, continue to stir for 11h, filter with suction, after the completion of the suction filter, beat with 400ml of ethanol solution with a mass fraction of 95% at 65°C 0.8h, lowered to 20°C, suction filtered, washed 3 times with ethanol solution with a mass fraction of 95% after the suction filtration, the amount of ethanol solution each time was 80ml, and then dried in a vacuum oven at 45°C to Constant weight obtains 89.3g trexagliptin succinate crude product;

[0023] 2) Take 1...

Embodiment 2

[0026] The purification method of the present embodiment trexagliptin succinate comprises the following steps:

[0027] 1) Preparation of crude trexagliptin succinate: take a reaction bottle, take 900ml of tetrahydrofuran and 126.9g of 2-({6-[(3R)-3-amino-1-piperidin-1-yl]-3 -Methyl-2,4-dioxo-3,4-dihydro-1(2H)-yl}methyl)-4-fluorobenzonitrile is added to the reaction flask, heated to 55°C until the added reactant is complete Dissolve, add 41.9g of succinic acid to react for 0.5h, then remove the heating device, cool down to room temperature, continue to stir for 10h, filter with suction, after the filtration is completed, beat with 600ml of ethanol solution with a mass fraction of 95% at 50°C 0.5h, lowered to 20°C, suction filtered, washed with absolute ethanol solution after suction filtration, and then dried to constant weight in a vacuum oven at 50°C to obtain 145.2g of trexagliptin succinate crude product;

[0028] 2) Take 10 g of the crude trexagliptin succinate prepared ...

Embodiment 3

[0031] The purification method of trexagliptin succinate in this example includes taking 10 g of the crude product of trexagliptin succinate prepared in step 1) of Example 1, and adding 80 ml of a mixed solvent of ethanol and isopropanol at a volume ratio of 7:1 , heated the oil bath to 80°C, beating for 1 hour, removed the oil bath, lowered the temperature to an internal temperature of 30°C, and kept stirring for 2.5 hours. After crystallization was completed, filter to obtain a filter cake, which was washed with absolute ethanol at a temperature of 8°C. After washing, Place in a vacuum oven at 40°C and dry to constant weight to obtain 9.2 g of white solid, which is complete.

[0032] The purification method of trexagliptin succinate in this example has a yield of 92%, and the purity of the white solid obtained after the purification is detected by HPLC is 99.82%.

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Abstract

The invention relates to the technical field of medicinal chemistry and in particular relates to a purification method of trelagliptin succinate. The purification method comprises the following steps: adding a trelagliptin succinate crude product into a mixed solvent prepared from ethanol and isopropyl alcohol according to the volume ratio of (5 to 7) to 1; heating and dissolving to obtain a crude product solution; cooling and recrystallizing the crude product solution; filtering to obtain a filter cake; washing the filter cake and drying to obtain the trelagliptin succinate. The purification method provided by the invention utilizes a manner that taking the ethanol and the isopropyl alcohol according to the volume ratio of (5 to 7) to 1 as the mixed solvent for re-dissolving and recrystallizing the trelagliptin succinate, thus effectively removing impurities in the trelagliptin succinate; the yield of a trelagliptin succinate pure product obtained by the whole purification method reaches 92 percent to 95 percent and the purity reaches 99.8 percent to 99.92 percent; meanwhile, the method provided by the invention is simple and convenient to operate and is applicable to industrial popularization and application.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a purification method of trexagliptin succinate. Background technique [0002] Trelagliptin is a dipeptidyl peptidase IV (DPP-4) inhibitor. DPP-4 is an enzyme that triggers the inactivation of incretins. Trexagliptin controls blood sugar in patients with type Ⅱ diabetes by selectively and persistently inhibiting DPP-4. This drug can not only achieve precise hypoglycemic effect at a lower economic cost, but also has obvious advantages in preventing hypoglycemia, cardiovascular risk and weight gain. It is mainly metabolized in the prototype form through bile and intestinal tract, and drug interactions The risk is small, and it can be safely used by patients at any stage of liver and kidney injury. Trexagliptin succinate (English name Zafatek) is an ultra-long-acting dipeptidyl peptidase IV (DPP-4) inhibitor that was approved for marketing by Japan's Takeda Pharmaceut...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 徐元李健
Owner ZHENGZHOU MINGZE MEDICAL TECH
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