Preparation method of alogliptin benzoate impurity

A technology for benzoic acid and impurities is applied in the field of preparation of alogliptin benzoate impurities, and achieves the effects of mild and controllable reaction conditions, reduced side reactions and high purity

Inactive Publication Date: 2018-01-09
山东淄博新达制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The existing literature and data have reported the synthetic route of alogliptin benzoate and related impurities of alogliptin benzoate, mainly including: 2-[[6-[(3S)-3-amino-1-piperidinyl ]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benz

Method used

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  • Preparation method of alogliptin benzoate impurity
  • Preparation method of alogliptin benzoate impurity
  • Preparation method of alogliptin benzoate impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] At 25°C, add 10.0g (62.3mmol) SM1, 40mL N-methylpyrrolidone, and 12.1g (93.6mmol) diisopropylethylamine into a 500mL three-necked flask in sequence, and then add the solution dropwise into the reaction flask under stirring. There is 40 mL of toluene solution of 13.4 g (68.4 mmol) SM2, after the dropwise addition, the temperature is raised to 70° C., and the reaction is carried out for 1.5 hours. The reaction system was lowered to room temperature, 40 mL of water was added thereto, stirred at 25° C. for 30 minutes, cooled to 0° C., stirred for 1 hour, and suction filtered. The filter cake was rinsed with 10 mL of isopropanol and then dried to obtain 15.5 g of off-white solid with a yield of 90.2%.

[0029] Add 5.5g (20mmol, 1eq) TM1 into 100mL tert-butanol, drop into 50mL aqueous solution of 5.0g (60mmol, 3eq) sodium bicarbonate at room temperature 25°C, and stir at room temperature 70°C for 12 hours.

[0030] Add concentrated hydrochloric acid dropwise to the system in...

Embodiment 2

[0032] The preparation of TM1 is the same as in Example 1.

[0033] Add 5.5g (20mmol, 1eq) TM1 into 100mL isopropanol, drop into 50mL aqueous solution of 5.0g (60mmol, 3eq) sodium bicarbonate at room temperature 25°C, and stir at room temperature 68°C for 16 hours.

[0034] Add concentrated hydrochloric acid dropwise to the system in a cold water bath at 10°C, adjust the pH to 5-6, remove isopropanol by rotary evaporation in a water bath at 40°C, add 100mL water and 100mL dichloromethane, separate the liquids, and extract the water phase with 100mL dichloromethane After three times, the combined organic phases were dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation in a water bath at 40°C to obtain a brown-red oil. Add 20mL of dichloromethane to dissolve the oil, add 80mL of isopropyl ether, freeze at -10°C, a solid precipitates, filter and dry at 40°C to obtain 1.4g of a yellow solid, content 99.1%, yield 23%.

Embodiment 3

[0036] The preparation of TM1 is the same as in Example 1.

[0037] Add 5.5g (20mmol, 1eq) TM1 into 100mL ethanol, drop into 50mL aqueous solution of 5.0g (60mmol, 3eq) sodium bicarbonate at room temperature 25°C, and stir at room temperature 73°C for 8 hours.

[0038] Add concentrated hydrochloric acid dropwise to the system in a cold water bath at 10°C, adjust the pH to 5-6, remove ethanol by rotary evaporation in a water bath at 40°C, add 100mL water and 100mL dichloromethane, separate the layers, extract the water phase with 100mL dichloromethane three times, After the combined organic phases were dried with anhydrous sodium sulfate, the solvent was removed by rotary evaporation in a water bath at 40°C to obtain a brown-red oil. Add 20mL of dichloromethane to dissolve the oil, add 80mL of isopropyl ether, freeze at -10°C, a solid precipitates, filter and air-dry at 40°C to obtain 2.1g of a yellow solid, content 98.8%, yield 34.5%.

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Abstract

The invention relates to a preparation method of alogliptin benzoate impurity and belongs to the technical field of pharmaceutical chemicals. The preparation method of alogliptin benzoate impurity provided by the invention comprises the following steps: (1) preparing TM1 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)cyanophenyl by taking 6-chloro-3-methylpyrimidin-2,4(1H,3H)-diketone as a raw material which reacts with 2-bromomethyl cyanophenyl; (2) preparing alogliptin benzoate impurity BP1 through a reaction between the TM1 and monohydric alcohol in an alkaline condition, wherein the structural formula of the BP1 is shown in the description. The preparation method provided by the invention is convenient to operate, the reaction conditions are mild and controllable,the side reactions are reduced, and therefore, the target product alogliptin benzoate is easy to separate and purify and has high purity.

Description

technical field [0001] The invention relates to a preparation method of alogliptin benzoate impurity, which belongs to the technical field of medicine and chemical industry. Background technique [0002] Alogliptin benzoate, chemical name: 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2 ,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile benzoate, the chemical structure is as follows: [0003] [0004] Alogliptin benzoate is a serine protease dipeptidyl peptidase IV (DPP-IV) inhibitor developed by Takeda Corporation of Japan. It has high selectivity and can maintain glucagon-like peptide 1 (GLP-1) and glucose in vivo. It depends on the level of insulin-promoting polypeptide (GIP), promotes the secretion of insulin, and thus exerts the hypoglycemic effect. In April 2010, it was approved by the Ministry of Health, Labor and Welfare of Japan. It is the fifth DPP-4 inhibitor approved in my country. For blood sugar control in patients with type 2 diabetes. [0005] The e...

Claims

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Application Information

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IPC IPC(8): C07D239/60
Inventor 吴照刚贾法强徐敏荣韩堃
Owner 山东淄博新达制药有限公司
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