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Preparation method of alogliptin or pharmaceutically acceptable salt of alogliptin

A pharmacy and concentrated hydrochloric acid technology, which is applied in organic chemistry, drug combination, metabolic diseases, etc., can solve the problems of difficult purification, recrystallization, and increased operating costs, and achieves cheap and easy-to-obtain raw materials, short reaction steps, and good environmental protection Effect

Inactive Publication Date: 2015-11-11
合肥信风科技开发有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] CN104447685A discloses a synthetic method of alogliptin. Although this method is synthesized with cheap and easy-to-obtain raw materials, the reaction steps are numerous, the operation cost is increased, the separation and purification are carried out many times in the middle, and the yield is low
[0009] There is another method for synthesizing alogliptin. The process route of this method is relatively simple, but the intermediate product needs to be recrystallized, and the yield is not high
Substituting (R)-3-aminopiperidine dihydrochloride directly makes the product more impurity and difficult to purify

Method used

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  • Preparation method of alogliptin or pharmaceutically acceptable salt of alogliptin
  • Preparation method of alogliptin or pharmaceutically acceptable salt of alogliptin
  • Preparation method of alogliptin or pharmaceutically acceptable salt of alogliptin

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] 1.45g (9mmol) 3-methyl-6-chlorouracil (compound of formula I) was added to the mixture of 2.12g (10.8mmol) 2-cyanobenzyl bromide (compound of formula II) and 1.87g (13.5mmol) of potassium carbonate In 30ml of tetrahydrofuran solution, heat to 70°C for reflux reaction for 6 hours, then add 1.87g (13.5mmol) of potassium carbonate, and simultaneously add 2.16g (10.8mmol) of (R)-3-Boc-aminopiperidine (compound of formula III) , heated to 80° C. for reflux reaction for 4 hours, and filtered while hot to remove excess inorganic salt insolubles such as potassium carbonate. Slowly add 3.5ml of concentrated hydrochloric acid to the filtrate, heat to 40°C and react for 2 hours, remove the Boc, cool, recover most of the tetrahydrofuran, let it stand still, a large amount of solids are precipitated, and filter with suction to obtain 3g of alogliptin hydrochloride The crude salt product was recrystallized with 9ml of ethanol to obtain 2.8g of pure alogliptin hydrochloride.

[0033]...

Embodiment 2

[0037]7.3g (45mmol) 3-methyl-6-chlorouracil (compound of formula I) was added to 10.6g (54mmol) of 2-cyanobenzyl bromide (compound of formula II) and 67.5mmol of sodium carbonate in 160ml of dimethyl formaldehyde In the amide solution, heat to 80° C. for reflux reaction for 5 hours, then add 67 mmol of sodium carbonate, and simultaneously add 11 g (54 mmol) (R)-3-Boc-aminopiperidine (compound of formula III), and heat to 70° C. for reflux reaction for 5 Hours, filtered while hot to remove excess inorganic salt insolubles such as sodium carbonate. Slowly add 18ml of concentrated hydrochloric acid to the filtrate, heat to 50°C and react for 2 hours, remove Boc, cool, recover most of the dimethylformamide, let it stand still, precipitate a large amount of solids, filter with suction, and obtain 15.5g of Ag The crude product of Gliptin hydrochloride was recrystallized with 47ml of ethanol to obtain 14g of pure alogliptin hydrochloride.

Embodiment 3

[0039] Add 58.4g (360mmol) of 3-methyl-6-chlorouracil (compound of formula I) to 86.3g (440mmol) of 2-cyanobenzyl bromide and 545mmol of potassium hydroxide in 1200ml of tetrahydrofuran solution, and heat to reflux at 80°C React for 6 hours, then add 550mmol potassium hydroxide, add 87g (435mmol) (R)-3-Boc-aminopiperidine (compound of formula III) at the same time, heat to 70 ℃ reflux reaction for 5 hours, filter while hot, remove Excessive potassium hydroxide and other inorganic salt insoluble matter. Slowly add 145ml of concentrated hydrochloric acid to the filtrate, heat to 50°C and react for 3 hours, remove Boc, cool, recover most of tetrahydrofuran, let it stand still, precipitate a large amount of solid, and filter with suction to obtain 128g of alogliptin hydrochloride The crude product was recrystallized with 448ml of ethanol to obtain 120g of pure alogliptin hydrochloride.

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Abstract

The invention provides a preparation method of alogliptin or a pharmaceutically acceptable salt of alogliptin. According to the preparation method, an acid-binding agent, a compound represented by a formula I, and a compound represented by a formula II are added into an organic solvent, and an obtained mixture is subjected to heating reflux reaction for a certain period of time; at the same time, the acid-binding agent and a compound represented by a formula III are added for heating reflux reaction for a certain period of time so as to obtain a compound represented by a formula IV, wherein R is used for representing a leaving group, and is selected from chlorine, bromine, iodine, or a sulfonate; and in the organic solvent, an acid is used for processing the compound represented by the formula IV so as to obtain alogliptin or the pharmaceutically acceptable salt of alogliptin. According to the preparation method, one-pot reaction is adopted, the preparation method is simple and convenient for operation; reaction steps are short; the raw materials are cheap and easily available; and the preparation method is suitable for industrialized large-scale production.

Description

technical field [0001] The invention relates to alogliptin, a drug for treating type II diabetes: 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl- A method for preparing 2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or a salt thereof. Background technique [0002] Diabetes mellitus (DM) is a heterogeneous and metabolic chronic or lifelong disease characterized by chronic hyperglycemia, which can cause atherosclerosis and is also an important risk of cardiovascular and cerebrovascular diseases and coronary heart diseases. factors, and even cause the death of the patient. There are currently about 285 million diabetic patients in the world, and it is estimated that the number of patients will increase to 300 million by 2025, and the total number of patients will exceed 471 million by 2035. DM has become the third chronic disease that seriously threatens human health after tumors and cardiovascular diseases. [0003] Alogliptin benzoate (Alogliptinbenzoate), the ch...

Claims

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Application Information

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IPC IPC(8): C07D401/04A61K31/513A61P3/10
CPCC07D401/04A61K31/513
Inventor 秦华利
Owner 合肥信风科技开发有限公司
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