Sitagliptin impurity synthesis method

A sitagliptin impurity and synthesis method technology, applied in the field of sitagliptin impurity synthesis, can solve the problems of long route, complex reaction, low yield, etc.

Active Publication Date: 2015-11-25
HEFEI HUAFANG PHARMA SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] A degraded impurity will be generated during the stability of the sitagliptin preparation, and its structure is shown in formula I. PCT application publication WO2010122578 has a report on this impurity, but does not disclose the synthesis method of this impurity. Chinese patent application publication CN201410612167 reports The synthetic method of this impurity, but this method route is longer, reaction is complicated, and intermediate preparation involves thionyl chloride and sulfuryl chloride toxic and corrosive substances, and intermediate preparation process is long, and yield is low; The inventive method has avoided The above shortcomings, and the sitagliptin impurity can be obtained without separation and purification of the preparative chromatographic column

Method used

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  • Sitagliptin impurity synthesis method

Examples

Experimental program
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Effect test

Embodiment 1

[0013] Embodiment 1: the preparation of sitagliptin impurity

[0014]

[0015] Put 5g of the compound shown in formula II into a 250ml three-neck flask, add 50ml of N,N-dimethylformamide, stir to dissolve, add 2ml of triethylamine, heat the system to 120°C, start the reaction, and track the reaction process by TLC , Reaction 12h. The system was cooled to room temperature, 100ml of water was added to the system, a white solid was precipitated, and the solid was filtered off to obtain 4.3g of sitagliptin impurity, with a yield of 91%.

Embodiment 2

[0017] Put 5g of the compound shown in formula II into a 250ml three-neck flask, add 50ml of N,N-dimethylacetamide, stir to dissolve, add 2ml of triethylamine, heat the system to 120°C, start the reaction, and track the reaction by TLC Process, reaction 12h. Cool the system to room temperature, add 100ml of ethyl acetate and 100ml of water to extract while stirring, wash the ethyl acetate layer with 100ml of saturated sodium chloride solution, dry the ethyl acetate solution with 5g of anhydrous sodium sulfate for 15-20min, and recover the solvent under reduced pressure get residue. The residue was dissolved in 50 ml, and 50 ml of n-hexane was added for crystallization to obtain 4.1 g of sitagliptin impurity as a solid, with a yield of 86%.

Embodiment 3

[0019] Put 5 g of the compound shown in formula II into a 250 ml three-neck flask, add 50 ml of toluene, stir to dissolve, 2 ml of triethylamine, heat the system to 110 ° C, reflux reaction, TLC detection to track the reaction process, and react for 24 hours. Cool the system down to room temperature, add 50ml of toluene and 100ml of water for extraction while stirring, wash the toluene layer with 100ml of saturated sodium chloride solution, dry the toluene solution with 5g of anhydrous sodium sulfate for 15-20min, and recover the solvent under reduced pressure to obtain a residue. The residue was dissolved in 50 ml, and 50 ml of n-hexane was added for crystallization to obtain 3.97 g of sitagliptin impurity as a solid, with a yield of 83%.

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PUM

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Abstract

The invention discloses a sitagliptin impurity synthesis method. According to the method, sitagliptin is taken as a raw material, and a sitagliptin impurity is obtained through a deamination reaction under an acidic or alkali condition. The purity of the sitagliptin impurity obtained according to the method can reach 99% or higher, and thus the sitagliptin impurity can serve as a reference substance for quality research.

Description

[0001] Field of the invention: the present invention relates to the field of organic chemistry, which is the elimination reaction of amino groups, specifically a method for synthesizing sitagliptin impurities. Background technique [0002] Sitagliptin was developed and marketed by Merck as the first dipeptidyl peptidase-4 (DPP-4) inhibitor. The drug was launched in the United States on October 16, 2006 and March 30, 2007 , the drug was approved by the US FDA in combination with metformin for the treatment of type 2 diabetes, and the drug has been marketed in many European countries. In August 2009, the drug was approved by the European Union as a first-line drug for the treatment of type 2 diabetes. In December 2009, Ono launched sitagliptin in Japan for the treatment of type 2 diabetes. In May 2011, Japan approved the drug in combination with alpha glucosidase inhibitors. In September 2011, Japan approved the drug Combination medication with insulin. [0003] The chemical n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 彭扶云高永好何勇吴宗好
Owner HEFEI HUAFANG PHARMA SCI & TECH
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