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Sitagliptin key intermediate impurity as well as preparation method and application thereof

A sitagliptin and intermediate technology, applied in the field of medicinal chemistry, can solve the problems of poor stability of key intermediates, quality decline, and affecting the quality of sitagliptin products, and achieve the goals of simple method, quality control and quality control Effect

Pending Publication Date: 2021-01-08
TAIZHOU BIOMEDICAL & CHEM IND RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In the actual production process of sitagliptin, the key intermediate 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2- Dimethyl-1,3-dioxacyclo-4,6-dione) (II) often needs to be stored according to the actual progress of production, however, due to the poor stability of the key intermediate (II), during storage It is easy to degrade during the process to produce intermediate impurities, which will lead to a decline in the quality of the key intermediate (II) product, and will generate new impurities in the subsequent production process, ultimately affecting the product quality of sitagliptin

Method used

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  • Sitagliptin key intermediate impurity as well as preparation method and application thereof
  • Sitagliptin key intermediate impurity as well as preparation method and application thereof
  • Sitagliptin key intermediate impurity as well as preparation method and application thereof

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preparation example Construction

[0030] The present invention provides the preparation method of sitagliptin key intermediate impurity described in above-mentioned technical scheme, comprises the following steps:

[0031] Mixing the acetylmycorrhizinic acid derivative having the structure shown in formula II with an organic solvent and performing pyrolysis to obtain the key intermediate impurity of sitagliptin having the structure shown in formula I;

[0032]

[0033] The organic solvent is one or more of toluene, xylene, chlorobenzene, chloroform, tetrahydrofuran, dioxane, DMF, DMSO and acetonitrile; the pyrolysis temperature is 100-120°C.

[0034] In the present invention, unless otherwise specified, the required preparation materials are commercially available products well known to those skilled in the art.

[0035] In the present invention, the chemical name of the acetyl-Merfuran's acid derivative having the structure shown in formula II is 5-(1-hydroxyl-2-(2,4,5-trifluorophenyl)ethylene)- 2,2-Dimet...

Embodiment 1

[0046]Take 1.4g of 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylene)-2,2-dimethyl-1,3-dioxacyclo-4,6-di Ketone) (II) was dissolved in 45mL (39g) of toluene, and after reflux at 110°C for 8h, the TLC detection should be completed, cooled to room temperature, and the solvent was recovered by distillation under reduced pressure, and the solvent was recovered with petroleum ether / ethyl acetate (volume ratio of 10: 1) Eluting with an eluent, and separating the obtained residue by column chromatography to obtain compound I-1.

[0047] The compound I-1 prepared in embodiment 1 is carried out nuclear magnetic characterization, and the characterization data of its proton nuclear magnetic resonance spectrum are as follows: 1 H-NMR (400MHz, CDCl 3 ): δ6.94(m,1H),6.87(m,1H),3.63(s,2H),2.16(s,3H). The chemical name of this compound is 1-(2,4,5-trifluoro phenyl)-2-propanone.

Embodiment 2

[0049] Take 1.0g of 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylene)-2,2-dimethyl-1,3-dioxacyclo-4,6-di Ketone) (II) was dissolved in 25mL (22g) of xylene, and after pyrolysis at 120°C for 6h at reflux, after the reaction was detected by TLC, it was cooled to room temperature, and the solvent was recovered by distillation under reduced pressure, and the solvent was extracted with petroleum ether / ethyl acetate (volume The ratio is 10:1) as the eluent for elution, and the obtained residue is separated by column chromatography to obtain compound I-2.

[0050] The compound 1-2 prepared in embodiment 2 is carried out nuclear magnetic characterization, and the characterization data of its proton nuclear magnetic resonance spectrum are as follows: 1 H-NMR (400MHz, CDCl 3 ): δ6.94(m,1H),6.87(m,1H),3.63(s,2H),2.16(s,3H). The chemical name of the compound is 1-(2,4,5-trifluorobenzene base)-2-propanone.

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Abstract

The invention provides a sitagliptin key intermediate impurity as well as a preparation method and application thereof, which belong to the technical field of medicinal chemistry. The compound with the structure as shown in the formula I provided by the invention is an impurity component generated in the production process of a key intermediate acetyl Meldrum's acid derivative 5-(1-hydroxy 2-(2, 4, 5-trifluorophenyl)ethylene)-2, 2-dimethyl-1, 3-dioxepin-4, 6-diketone) (II) for synthesizing sitagliptin. The impurity can be used as a reference substance to be applied to impurity analysis of keyintermediates in a sitagliptin production process so as to promote quality control of the key intermediates and further effectively control the quality of sitagliptin drugs. The invention provides thepreparation method of the sitagliptin key intermediate impurity, the synthesis method of the impurity reference substance of the sitagliptin key intermediate is established through pyrolysis, the method is a basis for researching impurity composition and quality control of sitagliptin, and the method is strong in operability and simple.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a sitagliptin key intermediate impurity and its preparation method and application. Background technique [0002] Sitagliptin was developed by Merck, and its phosphate salt (trade name Januvia) was approved for marketing in October 2006 as the first DPP-4 inhibitor, and was clinically used in the treatment of type II diabetes; in March 2007, the drug was combined with metformin Combination therapy for type II diabetes. Merck & Co., Ltd. has disclosed 5-(1-hydroxyl-2-(2,4,5-trifluorophenyl) ethylidene)-2,2-dimethyl-1,3-bis Oxygen-4,6-dione) (II) is a key intermediate, a method for synthesizing sitagliptin through multi-step reactions (Journal of the America Chemical Society, 2009, 131, 8798-8804), its synthetic route as follows: [0003] [0004] Among them, the chemical name of sitagliptin is (3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo ...

Claims

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Application Information

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IPC IPC(8): C07C49/233C07C45/60
CPCC07C49/233C07C45/60
Inventor 韩得满程格陈霞贺娇娇李培贤
Owner TAIZHOU BIOMEDICAL & CHEM IND RES INST CO LTD
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