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Conversion method for dimers

A compound and reaction system technology, applied in the field of conversion and utilization of dimer impurities, can solve the problems of increased production cost, low yield, affecting the quality of final product linagliptin and the like

Active Publication Date: 2014-11-05
SUNSHINE LAKE PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the preparation method of linagliptin obtained by using acid deprotection group, it is easy to generate a dimer impurity, which affects the quality of the final product linagliptin
If the impurities are directly removed and turned into by-products to give up, the yield will be lower and the production cost will be increased.

Method used

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  • Conversion method for dimers
  • Conversion method for dimers
  • Conversion method for dimers

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preparation example Construction

[0007] In the preparation process of linagliptin obtained by deprotecting the acid group, a dimer impurity compound (02) is easily generated, and its content can often exceed 5%. Its structure is shown in the following formula (02):

[0008]

[0009] Through research, the inventor has developed a method for converting the dimer impurity compound (02) into linagliptin, which can not only remove impurities, reduce by-products, but also increase the yield, which is beneficial to production and cost control.

[0010] The method for converting dimer impurity compound (02) into linagliptin, namely compound (1), comprises: under the condition of adding an alkaline reagent, compound (02) is converted into Linagliptin:

[0011]

[0012] The reaction solvent is: N,N-dimethylformamide, dichloromethane, toluene, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetone , butanone, 3-pentanone, ethyl acetate, water, or combinations ...

specific Embodiment approach

[0024] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.

[0025] The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.

[0026] In the present invention, g means gram, and mL means milliliter.

Embodiment 1

[0028] In the reaction flask, add 2.8 g of linagliptin crude product containing 13.8% dimer, add 15 mL of dichloromethane, add 1.5 mL of triethylamine to adjust the pH of the system to 8-9, heat to reflux for 24 hours, and detect by HPLC that it contains 1.36% dimer, stop heating, transfer to room temperature and stir for 0.5 hours, then cool to 0°C, crystallize for 1 hour, then filter and dry to obtain 2.5g of solid product linagliptin; HPLC detection product does not contain dimer.

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Abstract

The invention relates to a method for converting dimers of linagliptin into linagliptin. Under the alkaline condition that the pH value is not less than 8, dimers can be converted into a product linagliptin under the action of alkali, so that impurities are removed, and the yield is increased. The method is simple in process, reduces the production cost, and facilitates the industrial production.

Description

technical field [0001] The invention relates to a method for transforming and utilizing dimer impurities of medicines, belonging to the technical field of pharmacy. Background technique [0002] Linagliptin, a selective dipeptidyl peptidase 4 (DPP-4) inhibitor, can significantly control blood sugar, only need to be taken orally once daily, risk of hypoglycemia, cardiovascular events and weight gain Lower, the market prospect is better. The structure of linagliptin is shown in the following formula (1): [0003] [0004] In the preparation method of obtaining linagliptin by deprotecting the acid group, a dimer impurity is easily generated, which affects the quality of the final product linagliptin. If the impurities are directly removed and turned into by-products to give up, the yield will be lower and the production cost will be increased. If the impurity can be converted into the product linagliptin, it is beneficial to the quality control of the product and lower pr...

Claims

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Application Information

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IPC IPC(8): C07D473/04
CPCC07D473/04
Inventor 林碧悦肖清波
Owner SUNSHINE LAKE PHARM CO LTD
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