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Alogliptin benzoate preparation method

A technology of benzoic acid and formula, applied in the field of preparation of alogliptin benzoate, can solve the problems of difficult feeding, poor washing effect, low product purity, etc., to avoid corrosion of equipment, save production time, and improve reaction rate Effect

Active Publication Date: 2017-01-18
HEFEI LIFEON PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] 1. Slowly add water to the reaction solution, the precipitated solid is easy to agglomerate, has a high viscosity, and is easy to stick to the inner wall of the reaction vessel and the stirring slurry, and it is difficult to discharge the material, resulting in poor washing effect, low product purity, and is not suitable for industrial production
[0012] 2. The reaction solution is not filtered, and water is added directly. The product contains a large amount of inorganic salts, which needs to be washed with a large amount of purified water, resulting in a large amount of waste water and serious environmental pollution.
[0015] 1. Concentrated hydrochloric acid is used as the boc removal reagent. Because it contains a large amount of water, it is easy to cause hydrolysis of cyano groups and produce amide or carboxylic acid impurities, which are difficult to remove by standing
[0016] 2. After the Boc removal is completed, the solvent needs to be concentrated, especially dimethylformamide, which has a high boiling point and is not easy to concentrate and is not suitable for industrial production.

Method used

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  • Alogliptin benzoate preparation method

Examples

Experimental program
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Effect test

Embodiment 1

[0090] Embodiment 1: add 0.55 times of mass fraction 10% methanol solution and 3 times of water

[0091] Add 50mL (52g) of the intermediate IV reaction solution into a 250mL three-necked flask, turn on the mechanical stirring, heat up to 65°C, add 28.6g of 10% methanol solution first, no solid matter precipitates, cool down to 25°C, and a large amount of Solid, the solid is loose, does not form agglomerates, does not adhere to the wall, does not stick to the stirring paddle, slowly add 156g of water, stir and wash for 1 hour, filter, and blow dry at 60°C to constant weight to obtain 10.20g of intermediate IV, a pink solid, loss on drying 0.21%, using the HPLC area normalization method to measure the purity of 98.85%, the yield of 81.14%.

Embodiment 2

[0092] Embodiment 2: add 0.55 times of mass fraction 15% methanol solution and 3 times of water

[0093] Add 50mL (52g) of the intermediate IV reaction solution into a 250mL three-neck flask, turn on the mechanical stirring, heat up to 65°C, add 28.6g of 15% methanol solution first, no solids are precipitated, cool down to 25°C, and a large amount of solids are precipitated. The solid is loose, does not form agglomerates, does not adhere to the wall, does not stick to the stirring paddle, slowly add 156g of water, stir and wash for 1 hour, filter, and blow dry at 60°C to constant weight to obtain 10.30g of intermediate IV, a pink solid, with a loss on drying of 0.19% , using the HPLC area normalization method to measure the purity of 98.90%, the yield of 81.94%.

Embodiment 3

[0094] Embodiment 3: adding 0.55 times of mass fraction is 20% methanol solution and 3 times of water

[0095] Add 50mL (52g) of the intermediate IV reaction solution into a 250mL three-necked flask, turn on the mechanical stirring, heat up to 65°C, add 28.6g of 20% methanol solution first, no solids are precipitated, cool down to 25°C, and a large amount of solids are precipitated. The solid is loose, does not form agglomerates, does not adhere to the wall, does not stick to the stirring paddle, slowly add 156g of water, stir and wash for 1 hour, filter, and blow dry at 60°C to constant weight to obtain 10.32g of intermediate IV, a pink solid, with a loss on drying of 0.18% , the purity was 98.83% and the yield was 82.10% as measured by the HPLC area normalization method.

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Abstract

The present invention provides an alogliptin benzoate preparation method, which comprises treating an intermediate IV reaction solution, and specifically comprises: heating the intermediate IV reaction solution to a temperature of 50-80 DEG C, adding a diluted alcohol while hot, cooling to a temperature of 0-40 DEG C to make the crystal be crystallized, adding water after a lot of the crystals are crystallized, carrying out stirring washing, filtering, and drying to obtain the intermediate IV. According to the present invention, the intermediate IV is prepared by using the one-pot method, a certain amount of the diluted alcohol is added at the high temperature, the saturated solution is formed after the cooling, and the cooling is continuously performed to crystallize, such that the crystal caking problem caused by the direct water precipitation is avoided, the intermediate IV crystal is uniformly dispersed, sticking on the wall and the agglomeration do not exist, the sticking onto the stirring slurry does not exist, the operation is convenient, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of alogliptin benzoate. Background technique [0002] The chemical name of alogliptin benzoate is 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo -1(2H)-pyrimidinyl] methyl] benzonitrile benzoate, the structural formula is as follows: [0003] [0004] Alogliptin Benzoate, the chemical name is 2-((6-((3R)-3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3, 4-Dihydropyrimidin-1(2H)yl)methyl)benzonitrile benzoate is a new drug developed by Japan's Takeda Pharmaceutical for the treatment of type 2 diabetes. The drug is a serine protein dipeptidyl peptidase IV (DPP-IV) inhibitor, which can maintain the level of glucagon-like-1 peptide and glucose-dependent insulinotropic peptide in the body, increase insulin secretion, and thus exert Hypoglycemic effect. Clinical studies have shown that the drug is well tolerated by patients, with mild adverse r...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 裴林蒋运运李冰陈军高美华季俊虬
Owner HEFEI LIFEON PHARMA
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