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Preparation method of alogliptin intermediate

A technology for intermediates and preparation steps, applied in the field of preparation of alogliptin intermediates, can solve problems such as limiting total yield, and achieve the effect of improving yield

Inactive Publication Date: 2018-11-02
张正光
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Clearly, the yield of the synthesis of the intermediate compound 3 from the starting materials compound 1 and compound 2 limits the overall yield of the process

Method used

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  • Preparation method of alogliptin intermediate
  • Preparation method of alogliptin intermediate
  • Preparation method of alogliptin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Embodiment 1: the preparation of composite oxide

[0024] The preparation method is a hydrothermal method, specifically comprising the following steps:

[0025] Under vigorous stirring at room temperature, add 10mmol of zinc acetate, 5mmol of manganese acetate, 12g of polyvinylpyrrolidone and 8g of urea into a mixture of 120mL of deionized water and ethylene glycol and mix evenly, wherein: the volume ratio of deionized water to ethylene glycol The ratio was 2:1; after that, the obtained mixture was transferred to a stainless steel reaction kettle, and placed in a dry oven at 210°C for 20h. After the reaction kettle was cooled to normal temperature, it was filtered, washed, and samples were collected. Dry at 80°C for 12 hours in air, and calcined at 500°C for 4 hours to obtain a composite oxide.

[0026] The SEM characterization of the above composite oxide was observed on a JSM-7001F scanning electron microscope with a working voltage of 200kV. The powder sample was ...

Embodiment 2

[0027] Embodiment 2: prior art prepares intermediate compound 3

[0028] The raw material compound 1 (10.0 g, 68 mmol) was added to 100 ml of DMSO / DMF mixed solvent with a volume ratio of 1:1, and stirred at room temperature to dissolve. After being dissolved, 2.5 g of sodium hydride and 2.5 g of lithium bromide were added. The raw compound 2 (13.4g, 68mmol) was dissolved in 30ml of DMSO / DMF mixed solvent with a volume ratio of 1:1, and the solution of compound 2 was slowly added to the mixed solution of compound 1 under stirring conditions, and the reaction was stirred for 12h. The reaction solution was filtered and concentrated to obtain a crude product. After purification by silica gel column chromatography (dichloromethane / acetone, 75:25 isocratic elution), the intermediate compound 3 was obtained.

[0029] The dry weight of intermediate compound 3 was 9.2 g, and the yield was 51.7%.

Embodiment 3

[0030] Embodiment 3: the inventive method prepares intermediate compound 3

[0031] The raw material compound 1 (10.0 g, 68 mmol) was added to 100 ml of DMSO / DMF mixed solvent with a volume ratio of 1:1, and stirred at room temperature to dissolve. After being dissolved, 2.5 g of sodium hydride, 2.5 g of lithium bromide and 5 g of the composite oxide prepared in Example 1 were added. The raw compound 2 (13.4g, 68mmol) was dissolved in 30ml of DMSO / DMF mixed solvent with a volume ratio of 1:1, and the solution of compound 2 was slowly added to the mixed solution of compound 1 under stirring conditions, and the reaction was stirred for 12h. The reaction solution was filtered and concentrated to obtain a crude product. After purification by silica gel column chromatography (dichloromethane / acetone, 75:25 isocratic elution), the intermediate compound 3 was obtained.

[0032] The dry weight of intermediate compound 3 was 16.5 g, and the yield was 93.5%.

[0033] The difference b...

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Abstract

The invention discloses a preparation method of an alogliptin intermediate. The method comprises the following steps of adding 10.0g of raw material compound into 100ml of mixed solvent of DMSO (dimethyl sulfoxide) / DMF (dimethyl formamide) in a volume ratio of 1 to 1, stirring at normal temperature to dissolve, after dissolving, adding 2.5g of sodium hydride, 2.5g of lithium bromide and 5g of composite oxide; dissolving 13.4g of raw material compound 2 in 30ml of mixed solvent of DMSO / DMF in a volume ratio of 1 to 1, adding the solution of the compound 2 slowly into a mixed solution of the compound 1 in a stirring condition, and stirring to react for 12 hours; filtrating a reaction solution, and concentrating to obtain a crude product; purifying by using silica gel column chromatography, and then obtaining an intermediate compound 3. The composite oxide can be used for effectively catalyzing and synthesizing the alogliptin intermediate. The preparation method provided by the inventioneffectively improves the yield of the alogliptin intermediate.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis and relates to a preparation method of an alogliptin intermediate. Background technique [0002] Alogliptin benzoate (Alogliptin benzoate), the chemical name is (R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3 , 4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile benzoate, is a serine protease dipeptidyl peptidase IV (DPP-IV) inhibitor that maintains glucagon-like peptide in vivo 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels, promote the secretion of insulin, thereby exerting a hypoglycemic effect. Studies on diabetes drugs have found that drugs such as alogliptin benzoate have a good curative effect on type 2 diabetes and are well tolerated in clinical manifestations. Therefore, this type of drug has broad research prospects in the treatment of diabetes. [0003] The paper Discovery of Alogliptin: A Potent, Selective, Bioavailable, and Efficacious Inh...

Claims

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Application Information

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IPC IPC(8): C07D239/553
CPCC07D239/553
Inventor 张正光
Owner 张正光
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