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Preparation method of vildagliptin

A technology of compound and solvent, which is applied in the field of preparation of Vildagliptin, can solve the problems such as the decrease of yield, and achieve the effect of low cost and simple operation

Active Publication Date: 2014-08-13
SHANGHAI VIWIT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this route, the hydrolysis reaction can not only hydrolyze the formyl group, but also hydrolyze the amide bond and cyano group on the tetrahydropyrrole ring, resulting in a significant decrease in yield

Method used

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  • Preparation method of vildagliptin
  • Preparation method of vildagliptin
  • Preparation method of vildagliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044]

[0045]Add 1.68 grams of 3-amino-1-adamantanol, 10 milliliters of anhydrous methanol, and 1.18 grams of benzaldehyde to a 50-milliliter three-necked flask in sequence, heat up to reflux and stir the reaction. TLC (thin-layer chromatography) monitors the reaction until the raw material Transformation is complete, producing intermediates. After cooling down to 0°C, a total of 0.48 g of sodium borohydride was added in batches to the reaction system. After the addition, react at 0°C to 5°C for 1 to 2 hours. After the completion of the reaction was monitored by TLC (thin layer chromatography), the solvent was removed by rotary evaporation. 20 ml of water and 20 ml of ethyl acetate were added to the residue, and the layers were separated to obtain an organic phase. Then use 10 ml of ethyl acetate to extract the aqueous phase three times, combine the organic phases, wash once with 20 ml of saturated brine, dry over anhydrous sodium sulfate, concentrate to remove the solv...

Embodiment 2

[0050]

[0051] 0.26 grams of the product prepared in Example 1 (amino-protected adamantanol), 0.17 grams of (S)-(1)-(2-chloroacetyl)-pyrrolidine-2-carbonitrile, 0.13 gram of diisopropylethylamine, 0.017 gram of potassium iodide, nitrogen replacement several times, 2 milliliters of dichloromethane was added, the temperature was raised to reflux, and the reaction was stirred for 6 hours. The completion of the reaction was monitored by TLC. After cooling to room temperature, it was filtered, and the filtrate was spin-dried, and purified by silica gel column chromatography to obtain the target product with an ESI-MS value of 394.2 (M+1).

Embodiment 3

[0053]

[0054] 0.26 grams of the product prepared in Example 1 (amino-protected adamantanol), 0.17 grams of (S)-(1)-(2-chloroacetyl)-pyrrolidine-2-carbonitrile, 0.11 1 g of sodium carbonate, 0.01 g of sodium bromide, and several times of nitrogen replacement, 2 ml of acetonitrile was added, heated to reflux, and stirred for 6 hours. The completion of the reaction was monitored by TLC. After cooling to room temperature, it was filtered, and the filtrate was spin-dried, and purified by silica gel column chromatography to obtain the target product with an ESI-MS value of 394.2 (M+1).

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Abstract

The invention discloses a preparation method of vildagliptin, and the preparation method comprises the following steps: 1) in the presence of a first solvent and a reducing agent, a formula II compound reacts with a formula III compound to obtain a formula IV compound; 2) in the presence of a second solvent, an alkali and a halide, the formula IV compound reacts with a formula V compound to obtain a formula VI compound; and 3); in the presence of a third solvent, the vildagliptin is obtained by debenzylation of the formula VI compound. The preparation method avoids generation of bi-substituted and other by-products of synthesis methods in the prior art, has the advantages of simple operation and low cost, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a method for preparing medicine, in particular to a method for preparing Vildagliptin. Background technique [0002] The chemical name of vildagliptin is: (-)-(2S)-1-[[(3-hydroxytricyclo[3.3.1.1[3,7]]decane-1-yl)amino]acetyl]pyrrole Alkane-2-carbonitrile, its structural formula is as follows: [0003] [0004] Vildagliptin is a dipeptidylase type IV (DDPIV) inhibitor developed by Novartis, Switzerland, which can be used to treat type 2 diabetes, whether used alone or in combination with other antidiabetic drugs, can significantly It reduces the level of glycosylated hemoglobin, has good tolerance and no significant adverse reactions, and is a new diabetes drug with good application prospects. In September 2007, it was approved as a low-dose drug by the European Union, and it has also been approved in Brazil and Mexico. [0005] In the patent application WO2004092127 of Novartis, the patent application WO2010022690 of Zent...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 魏彦君王华孟周钧
Owner SHANGHAI VIWIT PHARMA CO LTD
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