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Preparation method of saxagliptin intermediate (A1)

A technology for intermediates and compounds, applied in the field of preparation of saxagliptin intermediates (A1), can solve the problems of many steps and low yields, and achieve the effects of simple operation, stable product quality and mild conditions

Inactive Publication Date: 2016-04-06
南京克瑞特科技信息咨询有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0029] Most of the methods for the synthesis of A1 reported above have more steps and lower yields.

Method used

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  • Preparation method of saxagliptin intermediate (A1)
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  • Preparation method of saxagliptin intermediate (A1)

Examples

Experimental program
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Effect test

Embodiment 1

[0045] Example 1: Adamantanone acid ( Ⅰ ) Preparation

[0046] Mg (2.6g, 0.11mol) was added to dry tetrahydrofuran (20mL), under the protection of nitrogen, according to the conventional Grignard reagent preparation, stirred vigorously, heated to 40 ℃, dropwise add bromoadamantane (21.4g, 0.1mol ) Dissolve in dry tetrahydrofuran (100mL), during which a weak reflux is formed. After the dripping is completed, reflux for 1 hour and cool to room temperature to form a Grignard reagent tetrahydrofuran solution.

[0047] In dry tetrahydrofuran (80mL) of diethyl oxalate (29.2g, 0.2mol), cool to -70℃, under nitrogen protection, slowly add the Grignard reagent tetrahydrofuran solution prepared above at this temperature to the solution After the dripping is completed in about 2h, continue to react at this temperature for 4h, slowly add 5mol / L NaOH solution (100mL), while the temperature gradually rises to room temperature, filter to remove insoluble materials, the filtrate continues to stir ...

Embodiment 2

[0048] Example 2: Adamantanone acid ( A1 ) Preparation

[0049] According to the method of introducing hydroxyl groups reported in the patent WO2012028721, after the above product is reacted with mixed acid, the crude product is recrystallized with water to obtain 11.7 g, the yield is 76%, and the melting point is 165-166°C. Purity: 99.2%; 1 HNMR(DMSO-d 6 ): δ=1.49-1.72 (m, 12H), 2.19 (s, 2H), 4.61 (br, 1H), 14.0 (br, 1H).

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Abstract

The invention discloses a preparation method of a saxagliptin intermediate (A1), and belongs to the field of chemical pharmacy. Adamantyloxoacetic acid is obtained through a Grignard reaction, hydrolysis and a mixed acid reaction with bromoadamantane as an initial raw material. The method has the advantages of simple and easy operation, high yield, small pollution, and suitableness for industrial production.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to a preparation method of a saxagliptin intermediate (A1). Background technique [0002] Saxagliptin is a highly efficient, selective and competitive dipeptidyl peptidase-IV (DPP-IV) inhibitor jointly developed by Bristol-Myers Squibb and AstraZeneca. Preclinical and clinical studies have confirmed its The curative effect is outstanding and the effect is long-lasting. It was approved by FDA in 2009 for the treatment of type 2 diabetes in adults, and its chemical structure is shown in Formula 1. [0003] [0004] Chemical structure of formula 1 saxagliptin (saxagliptin) [0005] There are many reports on the synthesis methods of saxagliptin, and most of the patents or documents on its synthesis (WO2011117393; WO2010032129; US20060035954; US2005090539; J.Med.Chem, 2005, 48, 5025-5037; Org.Process. Res.Dev, 2009, 13, 1169-1176) After the amidation reaction of adama...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/367C07C59/215C07C59/205C07C27/02
Inventor 张亚萍
Owner 南京克瑞特科技信息咨询有限公司
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