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Preparation method of alogliptin benzoate

A technology of benzoic acid and methyl, which is applied in the field of preparation of alogliptin benzoate, can solve the problems affecting the purity and yield of the target product, and achieve the effects of reducing difficulty, reducing losses, and reducing the generation of by-products

Inactive Publication Date: 2018-01-19
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] For the synthetic route of alogliptin benzoate, many routes have been disclosed, but due to the generation of impurities, the purity and yield of the target product are affected, and the synthetic process needs to be optimized

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] (1) 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 pour it into the reaction flask under stirring 40 mL of toluene solution in which 13.4 g (68.4 mmol) of SM2 was dissolved was added dropwise. After the addition was completed, the temperature was raised to 70° C., and the reaction was 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%. 1 HNMR (400MHz, DMSO-d 6 )δppm 7.90(d, J=7.6Hz, 1H), 7.71(t, J=7.8Hz, 1H), 7.52(t, J=7.8Hz, 1H), 7.42(d, J=8.0Hz, 1H), 6.24(s,1H), 5.39(s,2H), 3.19(s,3H).

[0028] (2) Add 11.3g (65.3mmol) SM3, 22.5mL water, and 39.5g (470.2mmol) sodium bicarbonate t...

Embodiment 2

[0031] (1) At 25°C, add 10.0g (62.3mmol) SM1, 48mL N-methylpyrrolidone, and 16.1g (124.6mmol) diisopropylethylamine into a 500mL three-necked flask in sequence, and then pour it into the reaction flask under stirring 40 mL of toluene solution in which 18.3 g (93.5 mmol) of SM2 was dissolved was added dropwise. After the dropwise addition was completed, the temperature was raised to 73° C. and reacted for 3 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 14.5 g of off-white solid with a yield of 84.4%.

[0032] (2) Add 11.3g (65.3mmol) SM3, 30mL water, and 54.9g (653.0mmol) sodium bicarbonate to a 500mL reaction flask in sequence at 25°C, and stir for 30 minutes at this temperature. At 25°C, 75 mL of tetrahydrofuran and 15.0 g (54.4 mmol) of TM1 were added to the ...

Embodiment 3

[0035] (1) At 25°C, add 10.0g (62.3mmol) SM1, 32mL N-methylpyrrolidone, and 8.1g (62.3mmol) diisopropylethylamine into a 500mL three-necked flask in sequence, and then add 40 mL of toluene solution in which 12.2 g (62.3 mmol) of SM2 was dissolved was added dropwise. After the dropwise addition was completed, the temperature was raised to 68° C., and the reaction was carried out for 1 hour. 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 11.6 g of off-white solid with a yield of 67.5%.

[0036] (2) Add 11.3g (65.3mmol) SM3, 15mL water, and 22.8g (272.0mmol) sodium bicarbonate to a 500mL reaction flask in sequence at 25°C, and stir for 30 minutes at this temperature. At 25°C, 75 mL of acetonitrile and 15.0 g (54.4 mmol) of TM1 were added to the reaction flask. The temper...

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Abstract

The invention relates to a preparation method of alogliptin benzoate and belongs to the technical field of the pharmaceutical and chemical industry. The preparation method comprises the following steps: (1) taking 6-chlorine-3-methylpyrimidine-2,4(1H,3H)-diketone as the raw material, reacting with 2-brooethyl cyanophenyl to prepare TM1; (2) enabling the TM1 and (R)-3-amino piperidine dihydrochloride to react under the alkaline condition by taking a polar non-proton substance and water as solvents to prepare (R)-2-((6-(3-aminopiperidine-1-base)-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-base)-methyl) cyanophenyl(TM2); and (3) enabling the TM2 to react with the benzoic acid to prepare alogliptin benzoate. The preparation method is simple and convenient to operate, the occurrence of sideeffects is reduced, the reaction yield and the purity of a target product are increased, and the preparation method is favorable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of alogliptin benzoate, 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] For the synthe...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07C63/06C07C51/41
Inventor 吴照刚贾法强杨洪庆孙通
Owner 山东淄博新达制药有限公司
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