Preparation method for degraded trelagliptin impurity

A technology of impurities and methyl groups, which is applied in the preparation of trexagliptin to degrade impurities, and can solve problems such as the impact on drug quality

Active Publication Date: 2017-05-17
GUANGZHOU BAIYUSN GUANGHUA PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Impurities are easily produced during the synthesis of drugs and during drug degradation, which can have a serious impact on the quality of drugs

Method used

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  • Preparation method for degraded trelagliptin impurity
  • Preparation method for degraded trelagliptin impurity
  • Preparation method for degraded trelagliptin impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl ]Methyl]-5-fluorobenzonitrile (20.0g, 39.8mmol) was added to 100ml of dichloromethane, 30% hydrogen peroxide (22.5g, 199mmol) was added, then concentrated sulfuric acid (0.8g, 8.0mmol) was added and phase Transfer catalyst tetrabutylammonium bromide (1.29g, 4.0mmol), react at 30°C for 20h. After the reaction was completed, the pH of the reaction solution was adjusted to about 8 with saturated sodium carbonate solution, and the layers were separated. The aqueous phase was extracted with dichloromethane (30ml×3), and the organic phases were combined and concentrated under reduced pressure. Silica gel column chromatography (developing solvent: dichloromethane: isopropanol = 4:1) gave 15.2 g of a white solid, namely 2-[[6-[(3R)-3-amino-1-piperidinyl]- 3,4-Dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-5-fluorobenzamide, yield 73.3%, purity 98.9%.

[0043] 1 H-NMR(DMSO,400M)δ:8.41(s,...

Embodiment 2

[0046] 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl ]Methyl]-5-fluorobenzonitrile (20.0g, 39.8mmol) was added in 100ml of dichloromethane, 30% hydrogen peroxide (22.5g, 199mmol) was added, then formic acid (0.9g, 19.9mmol) was added and phase transfer Catalyst Tetrabutylammonium bromide (1.29g, 4.0mmol), react at 30°C for 30h. After the reaction was completed, the pH of the reaction solution was adjusted to about 8 with saturated sodium carbonate solution, and the layers were separated. The aqueous phase was extracted with dichloromethane (30ml×3), and the organic phases were combined and concentrated under reduced pressure. Silica gel column chromatography (developing solvent: dichloromethane: isopropanol = 4:1) gave 14.8 g of a white solid, namely 2-[[6-[(3R)-3-amino-1-piperidinyl]- 3,4-Dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-5-fluorobenzamide, yield 71.3%, purity 98.2%.

Embodiment 3

[0048] 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl ]Methyl]-5-fluorobenzonitrile (20.0g, 39.8mmol) was added to 100ml of ethanol, 30% hydrogen peroxide (22.5g, 199mmol) was added, concentrated sulfuric acid (0.8g, 8.0mmol) was added, and the reaction was carried out at 30°C 20h. After the reaction, adjust the pH of the reaction solution to about 8 with saturated sodium carbonate solution, concentrate under reduced pressure, add 50ml of water and 100ml of dichloromethane and stir for 10min, separate layers, extract the aqueous phase with dichloromethane (30ml×3), and combine the organic phases , concentrated under reduced pressure. Silica gel column chromatography (developing solvent: dichloromethane: isopropanol = 4:1) gave 15.6 g of a white solid, namely 2-[[6-[(3R)-3-amino-1-piperidinyl]- 3,4-Dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-5-fluorobenzamide, yield 75.2%, purity 98.5%.

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Abstract

The invention relates to a preparation method for degraded trelagliptin impurity. The method comprises the following steps: adding 2-[[6-[(3R)-3-amino-1-piperidyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidyl] methyl]-5-fluorobenzonitrile, an oxidizing agent and an acid catalyst into an organic solvent, and then reacting for 6-48h, thereby acquiring the degraded trelagliptin impurity, namely, 2-[[6-[(3R)-3-amino-1-piperidyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidyl] methyl]-5-fluorobenzamide, wherein the organic solvent is selected from at least one of C1-C4 alcohol, C2-C6 ether, tetrahydrofuran and dichloromethane and the oxidizing agent is selected from at least one of hydrogen peroxide, metachloroperbenzoic acid, t-butylhydroperoxide and peracetic acid. The method has the advantages of few steps, simple operation, mild reaction condition, and high product yield and purity.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to a preparation method of trexagliptin for degrading impurities. Background technique [0002] Trexagliptin succinate, chemical name 2-({6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo Dai-1(2H)-pyrimidinyl}methyl)-4-fluoro-benzonitrile succinate, the chemical structure is: [0003] [0004] Trexagliptin succinate is a dipeptidyl peptidase IV (DPP-4) inhibitor, which controls blood sugar levels through selective and sustained inhibition of DPP-4. On March 26, 2015, Japan's Takeda Corporation announced that the new diabetes drug Zafatek (trelagliptin succinate, trelagliptin succinate) was approved by the Japanese Ministry of Health, Labor and Welfare (MHLW) for the treatment of type 2 diabetes. This approval marks that Zafatek has become the first oral once-weekly hypoglycemic drug marketed in the world. [0005] The patent CN1926128A applied by Takeda Corporat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 江志强何敏儿葛婷张新萍辜喜隆戴艳萍
Owner GUANGZHOU BAIYUSN GUANGHUA PHARMA
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