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Method for preparing sitagliptin phosphate anhydrous crystal form I

A technology of sitagliptin phosphate and anhydrous crystals, which is applied in the field of pharmaceutical chemical crystallization, can solve problems such as high drying temperature, high crystallization temperature, and complicated process operation, and achieve industrial production, mild reaction conditions, and simple process operation Effect

Active Publication Date: 2013-12-04
ZHEJIANG HISOAR PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although CN1845674A gives the characteristic X-ray diffraction spectrum, characteristic DSC curve and thermogravimetric analysis (TG) curve of Sitagliptin Phosphate Anhydrous Form I, it does not provide the preparation examples of Anhydrous Form I
The quality standard of mixed crystals is difficult to establish, thus the application of mixed crystals also makes the quality control of preparations difficult
In addition, the crystallization temperature in CN1845674A is as high as the boiling point of the solvent, the drying temperature is high, energy consumption is high, and the process operation is complicated, which is not conducive to industrial production

Method used

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  • Method for preparing sitagliptin phosphate anhydrous crystal form I
  • Method for preparing sitagliptin phosphate anhydrous crystal form I
  • Method for preparing sitagliptin phosphate anhydrous crystal form I

Examples

Experimental program
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Effect test

preparation example Construction

[0066] The preparation process of sitagliptin free base is:

[0067]

[0068] Add 20 mL of acetonitrile to a 50 mL round bottom flask, add (3R)-3-[(1,1-dimethylethoxycarbonyl)-amino]-4-(2,4,5-trifluorophenyl) butane acid (3.32g, 0.01mol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-α]piperazine hydrochloride ( 2.28g, 0.01mol), the temperature of the reaction system was cooled to 0°C with an ice-salt bath, and 1-hydroxybenzotriazole (HOBT) (1.62g, 0.012mol), 1-ethyl-3-(3- Dimethylaminopropyl) carboximide hydrochloride (EDC·HCl) (2.29g, 0.012mol), add 3g of triethylamine dropwise, stir and react at room temperature for 24h, wash the reaction solution with 3×20mL distilled water, and the organic layer Dry over anhydrous magnesium sulfate for 1 hour, filter off the desiccant, and concentrate to obtain 4.81 g of product. 1 H NMR (500MHz, CDCl 3 )δ7.08(dd,J=16.7,8.8Hz,1H),6.98-6.75(m,1H),5.33(d,J=8.6Hz,1H),4.95(s,2H),4.18(s,4H ),3.99(s,1H),2.82(dd,J=128.2,7.2H...

Embodiment 1

[0077] At room temperature, take 1.25g of sitagliptin phosphate anhydrous crystal form IV and add 25mL of acetone to obtain a solid suspension of sitagliptin phosphate, stir the solid suspension at 10°C for 24h, filter the obtained crystal slurry, wash with acetone, and filter the cake Placed in a vacuum oven at 50°C and dried for 6 hours to obtain anhydrous crystal form I of sitagliptin phosphate (yield: 92.0%).

Embodiment 2

[0079] At 40°C, take 1.25g of amorphous sitagliptin phosphate and add 50mL of acetone to obtain a solid suspension of sitagliptin phosphate, then add 62.5mg of sitagliptin phosphate anhydrous form I seed crystals with stirring at 40°C, and stir for 12h , filtered the obtained crystal slurry, washed with acetone, and dried the filter cake in a vacuum oven at 40°C for 2 hours to obtain anhydrous crystal form I of sitagliptin phosphate (yield: 92.5%).

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Abstract

The present invention relates to a method for preparing an anhydrous crystal form I of sitagliptin phosphate. The method comprises: crystallizing by stirring a suspension of sitagliptin phosphate solid at a crystallization temperature, then separating the crystallized crystals, washing, and drying so as to obtain an anhydrous crystal form I of the sitagliptin phosphate, wherein the solvent for the suspension of the sitagliptin phosphate solid is selected from acetone or acetonitrile, or the solvent for the suspension of the sitagliptin phosphate solid is selected from a mixture of a C1-4 alkanol and water, a mixture of ethylene glycol and water, a mixture of acetone and water, or a mixture of acetonitrile and water. A single crystal form of sitagliptin phosphate in an anhydrous crystal form I can be prepared by the method of the present invention. The method facilitates the control of product quality and the establishment of a quality standard, and has advantages such as a simple and convenient crystallization process, mild reaction conditions, and a high product yield without a high temperature reaction for a long time.

Description

technical field [0001] The invention relates to the technical field of medicinal chemical crystallization, in particular to a method for preparing anhydrous crystal form I of sitagliptin phosphate in a single crystal form. Background technique [0002] Sitagliptin phosphate is the first dipeptidyl peptidase-4 (DPP-4) inhibitor approved clinically for the treatment of type 2 diabetes, which can prevent and treat type 2 diabetes, hyperglycemia, insulin resistance, obesity and hyperlipidemia Blood pressure and certain complications. Sitagliptin Phosphate was developed by Merck and launched in Mexico and the United States in 2006, and was approved by the European Union for the treatment of type 2 diabetes in 2007. At present, sitagliptin phosphate tablets have become the second largest oral diabetes drug in the United States. [0003] Dipeptidyl peptidase-4 (DPP-4), a novel target for the treatment of type 2 diabetes, rapidly inactivates incretin glucagon-like peptide-1 (GLP-1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/4985A61P3/10A61P5/50A61P3/04A61P9/12
CPCC07D487/04A61P3/04A61P3/10A61P5/50A61P9/12
Inventor 李永新盛晓霞张群辉黄光东
Owner ZHEJIANG HISOAR PHARMA
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