Preparation process of vildagliptin impurity

A vildagliptin impurity and process technology, applied in the field of drug synthesis, can solve the problems of expensive raw materials, complicated operation and the like

Pending Publication Date: 2020-12-25
CHONGQING MEDICAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] The problem to be solved by the present invention is to overcome the existing vildagliptin impurity namely 2-(3-hydroxyadamantan-1-yl)hexahydropyrrole[1,2-a]piperazine-1,4-dione In the preparation method, the raw materials are expensive, the operation is complicated and other technical problems, and a method for preparing 2-(3-hydroxyadamantan-1-yl)hexahydropyrrole[1,2-a]piperazine-1,4-dione is provided The new process of the present invention, the method raw material of the present invention is cheap and easy to obtain, and operation is simple, and reaction step is short, and reaction process does not involve expensive catalyst, and reaction condition is mild and easy to control, has avoided polluting environment

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  • Preparation process of vildagliptin impurity
  • Preparation process of vildagliptin impurity
  • Preparation process of vildagliptin impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Preparation of Compound 1

[0025] 4g (0.034mol) L-proline is packed in the 100ml round-bottomed flask, and reaction bottle is placed under ice bath condition, N 2 Slowly add 11.05ml (0.138mol) of chloroacetyl chloride dropwise under protection into the reaction flask, and react for 10 minutes after the drop is completed. The temperature was raised to 70° C. and stirred under reflux for 1.5 h. After the reaction was completed, cool to room temperature, add 10ml of water to the reaction flask to dilute and stir for 20min. Then, 30 ml of saturated brine and 50 ml of ethyl acetate were added for extraction, and the organic layer was collected. The aqueous layer was repeatedly extracted with 60 ml of ethyl acetate. The organic layers were combined and dried by adding anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain a pale yellow oil, which was crystallized by adding isopropyl ether dropwise under ice-bath conditions, and dried by sucti...

Embodiment 2

[0027] Preparation of Compound 2

[0028] Add 1.4g (0.008mol) of 3-amino-1-adamantanol, 1.7ml of triethylamine, and 0.15g of KI into 40ml of tetrahydrofuran, stir to dissolve, and control the temperature at 40°C. A solution of 2.3 g (0.012 mol) of compound 1 dissolved in 20 ml of tetrahydrofuran was slowly added dropwise through the dropping funnel, and added dropwise to the reaction flask at a constant speed within 30 min. After dripping, it was heated to reflux for 4 hours. After the reaction was completed, it was cooled to room temperature and filtered. The filtrate was distilled off under reduced pressure to remove the organic solvent. The residue was recrystallized with ethyl acetate, filtered and dried to obtain 1.88 g of compound 2 as a white solid, yield: 73.8%. m.p.200.8-203.4°C; ESI-MS (m / z): 323 [M+H]+.

Embodiment 3

[0030] Preparation of vildagliptin impurity 2-(3-hydroxyadamantan-1-yl)hexahydropyrrole[1,2-a]piperazine-1,4-dione

[0031] Add 3.6g (0.01mol) of compound 2 and 40ml of DMF into a 100ml reaction flask and stir to dissolve, then add 2.02g of triethylamine dropwise under ice cooling. After dropping, the reaction bottle was transferred to -10°C, N 2 Under protection, slowly drop 2.73g (0.02mol) isobutyl chloroformate into the reaction flask. After dropping, keep at -10°C for 30 minutes, then rise to room temperature for 1 hour. After the reaction was completed, add 50ml of water to quench and continue to stir for 20min, extract with 50ml of ethyl acetate solution, collect the organic layer, then repeatedly extract the water layer with 60ml of ethyl acetate, combine the organic layers, and add anhydrous sodium sulfate to dry. Suction filtration, rotary evaporation to remove the organic solvent to obtain an oil, crystallization with acetone, filtration, and drying to obtain the i...

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Abstract

The invention discloses a preparation process of a vildagliptin impurity, namely 2-(3-hydroxy adamantane-1-yl) hexahydropyrrole [1, 2-a] piperazine-1, 4-diketone. According to the process, L-proline is used as an initial raw material, and 2-(3-hydroxy adamantane- 1-yl) hexahydropyrrole [1, 2-a] piperazine-1, 4-diketone is prepared through secondary N-chloracetylation reaction, amino substitution and intramolecular cyclization. The method is mainly characterized in that reaction steps and time are shortened, and expensive catalysts and tedious operation means are not involved in the whole reaction process. The preparation process has the advantages of easily available raw materials, mild and easily controllable reaction conditions and high product purity, and the vildagliptin impurity can be used as a reference substance for vildagliptin bulk drug quality control.

Description

technical field [0001] The invention relates to a process for preparing vildagliptin impurity, 2-(3-hydroxyadamantan-1-yl)hexahydropyrrole[1,2-a]piperazine-1,4-dione, which belongs to drug synthesis field. Background technique [0002] Diabetes is a long-term chronic metabolic disease and has become one of the three major threats to human health in the 21st century, seriously affecting the quality of life of patients. In recent years, the incidence of diabetes has increased rapidly. According to relevant data reports, by 2017, about 451 million people around the world suffer from diabetes. Moreover, this number is still rising and will even reach 693 million by 2045. Vildagliptin (structural formula below) designed by Novartis is a highly selective, reversible orally active dipeptidyl peptidase IV (DPP-IV) inhibitor for the treatment of type 2 diabetes. The product enhances the sensitivity of α and β cells to blood sugar by controlling the degradation of glucagon, and in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 胡湘南蔡林宏张立官晓书边煦霏廖琦李毓飞
Owner CHONGQING MEDICAL UNIVERSITY
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