Method for preparing trelagliptin

A compound and reaction solvent technology, applied in the field of preparation of troxagliptin, can solve problems such as difficult removal, multiple impurities, and high RAPD dosage, and achieve the effects of improving yield and purity, reducing the generation of impurities and improving the reaction yield.

Active Publication Date: 2016-04-27
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] This method needs to adopt tube sealing reaction, which is not suitable for large-scale industrial production. The amount of RAPD is too much, and because the reaction temperature is too high, the energy consumption

Method used

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  • Method for preparing trelagliptin
  • Method for preparing trelagliptin
  • Method for preparing trelagliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1 Preparation of Trexagliptin

[0032] Add 930.0g of No. I substance, 3.0g of RAPD60, and 3.72L of acetonitrile into a 10L three-necked flask, cool down to below 10°C, and add DBU2122g dropwise. After the addition, the temperature was raised to 10-20°C, and the reaction was kept for 3 hours. Mix the reaction liquid with 15 kg of ice water, then add 5.0 L of dichloromethane, adjust the pH to 1-4 with 4M hydrochloric acid, separate the liquids, wash the water phase with 5.0 L of dichloromethane; combine the water phases, add 5.0 L of dichloromethane, Adjust the pH to 8-10 with saturated potassium carbonate solution, separate the layers, extract the aqueous phase with 5.0 L of dichloromethane, combine the organic phases, dry, filter, and concentrate to obtain the crude product No. II.

[0033] Add crude trexagliptin and 5500ml of isopropanol to the 10L reaction flask, stir and heat to reflux, and dissolve slowly. After dissolving, remove the oil bath, lower the ...

Embodiment 2

[0035] Example 2 Preparation of Trexagliptin

[0036] Add 93.0g of No. I substance, 60.3g of RAPD, and 372mL of N-methylpyrrolidone into a 1L three-necked flask, cool down to below 10°C, and add 212.2g of DBU dropwise. After the addition, the temperature was raised to 20-30°C, and the reaction was kept for 3 hours. Mix the reaction solution with 1.5kg of ice water, add 500mL of n-hexane, adjust the pH to 2-3 with 4M hydrochloric acid, separate the liquids, wash the water phase with 500mL of n-hexane; combine the water phases, add 500mL of ethyl acetate, saturated potassium carbonate solution Adjust the pH to 8-9, separate the liquids, extract the aqueous phase with 500m of ethyl acetate, combine the organic phases, dry, filter, and concentrate to obtain the crude product of No. II.

[0037] Add the crude trexagliptin and 550ml of tetrahydrofuran into the 1L reaction flask, stir and heat to reflux, and dissolve slowly. After dissolving, remove the oil bath, lower the temper...

Embodiment 3

[0039] Example 3 Preparation of Trexagliptin

[0040] Add 93.0g of No. I substance, 60.3g of RAPD, 372mL of N,N-dimethylacetamide into a 1L three-necked flask, cool down to below 10°C, and add 159.1g of DBU dropwise. After the addition, the temperature was raised to 30-40°C, and the reaction was kept for 2 hours. Mix the reaction solution with 1.5kg of ice water, add 500mL of ethyl acetate, adjust the pH to 1-2 with 4M hydrochloric acid, separate the liquids, wash the water phase with 500mL of ethyl acetate; combine the water phases, add 500mL of dichloromethane, and Adjust the pH of the sodium solution to 9-10, separate the liquids, extract the aqueous phase with 500 mL of dichloromethane, combine the organic phases, dry, filter, and concentrate to obtain the crude product No. II.

[0041] Add the crude trexagliptin and 550ml of acetonitrile into the 1L reaction flask, stir and heat to reflux, and dissolve slowly. After dissolving, remove the oil bath, lower the temperatu...

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Abstract

The invention relates to a method for preparing trelagliptin. The method comprises the following steps: 1) in a reaction solvent, adding 2-(6-chlorine-3-methyl-2,4-dione-3,4-dihydropyrimidine-dihydro-1-methyl)-4-F-benzonitrile into R-3-piperidinamine dihydrochloride, dropwise adding 1,8-diazabicyclo[5,4,0]-undec-7-ene in ice bath, at temperature of 15-25 DEG C, insulating the materials for reacting for 2 hours, 2) using hydrochloric acid to adjust a reaction solution to acidity, 3) adding an organic solvent and adjusting a pH value of a water phase to alkalescence, extracting the material to obtain a trelagliptin crude product, and 4) using a solvent for recrystallization to obtain trelagliptin. The obtained trelagliptin can effectively control chromatographic purity being no less than 99.0% and yield being no less than 75%, process is simple, and cost is low.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for preparing 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] CN101360723A discloses a method for preparing trexagliptin, the reaction formula is as follows: [0006] This method needs to adopt tube sealing reaction, which is not suitable for large-scale industrial production. The amount of RAPD is too much, and because the reaction temperature is too high, the energy consumption is also high, and more impurities are generat...

Claims

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Application Information

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IPC IPC(8): C07D401/04
Inventor 张小成但春燕张上华杨巧宾左小勇张耀春雷皇书
Owner CHONGQING PHARMA RES INST
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