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Preparation process of alogliptin benzoate

A preparation process, the technology of benzoic acid, applied in the direction of organic chemistry, can solve the problems of harmful gas unfavorable environmental protection, unfavorable large-scale production and industrial operation, affecting product quality, etc., achieve efficient green environmental protection process methods, optimize synthetic routes and Effects of process, simplified synthetic route and process

Inactive Publication Date: 2018-11-30
JINLIN MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] This route has low requirements on equipment, long route history, many reagents used, large loss in actual operation, and a total yield of 31.5%. The generation of harmful gases is not conducive to environmental protection, and its instability in the condensation reaction process leads to Unavoidable side reactions will affect product quality. It needs to be separated and purified by column chromatography. The operation is cumbersome, which is not conducive to large-scale production and industrial operation.

Method used

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  • Preparation process of alogliptin benzoate
  • Preparation process of alogliptin benzoate
  • Preparation process of alogliptin benzoate

Examples

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Effect test

Embodiment 1

[0035] Synthesis of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile (compound 1)

[0036] 96.36 g of 3-methyl-6-chlorouracil, 129.36 g of 2-cyanobenzyl bromide, 45.54 g of triethylamine, 80 o Stir the reaction at about C, cool down to room temperature, add purified water, stir, crystallize, suction filter, and dry to obtain 146.62 g of the product, mp: 164.6-166.5 o C.

[0037] 1H-NMR (500 MHz, CDCl 3 ) δ: 7.71 (dd, J = 7.7 Hz, 1.3 Hz, 1H), 7.60 (td, J = 7.7Hz, 1.4Hz, 1H), 7.43(td, J = 7.6 Hz, 1.1 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 6.02 (s, 1H), 5.52 (s, 2H), 3.39 (s, 3H); MS m / z : 276.1[M+H] + , 298.0[M+Na] + .

[0038] 3.3 (R)-2-[(6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl ) Synthesis of methyl] benzonitrile

[0039] Stir in absolute ethanol and add (compound ) 119.45 g and ( R )-3-aminopiperidine dihydrochloride 82.53 g, sodium bicarbonate 181.56 g, 80 o C to heat and reflux for 6 hours...

Embodiment 2

[0051] Synthesis of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile (compound )

[0052] 62.54 g of 3-methyl-6-chlorouracil, 93.43 g of 2-cyanobenzyl bromide, 31.34 g of triethylamine, 80 o Stir the reaction at about C, cool down to room temperature, add purified water, stir, crystallize, suction filter, dry, and obtain 108.34 g of the product, mp: 164.6-166.5 o C.

[0053] 1 H-NMR (500 MHz, CDCl 3 ) δ: 7.71 (dd, J = 7.7 Hz, 1.3 Hz, 1H), 7.60 (td, J = 7.7Hz, 1.4Hz, 1H), 7.43(td, J = 7.6 Hz, 1.1 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 6.02 (s, 1H), 5.52 (s, 2H), 3.39 (s, 3H); MS m / z : 276.1[M+H] + , 298.0[M+Na] + .

[0054] 3.3 (R)-2-[(6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl ) Synthesis of methyl] benzonitrile

[0055] Add (compound 1) 70.54g and ( R )-3-aminopiperidine dihydrochloride 59.43 g, sodium bicarbonate 154.28 g, 80 o C to heat and reflux for 6 hours, cool down, filter with suction,...

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Abstract

The invention discloses a preparation process of alogliptin benzoate, wherein the preparation process comprises the steps: carrying out nucleophilic substitution of 3-methyl-6-chlorouracil and 2-cyanobromobenzyl under alkaline conditions to obtain 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl methyl)-benzonitrile (a compound 1); then substituting with (R)-3-aminoperidol dihydrochloride to obtain (R)-2-[(6-(3-aminoperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]benzonitrile (a compound 2); and finally, salifying with benzoic acid to obtain alogliptin benzoate (a compound 3), determining the structure of the target compound at each step by MS and 1H-NMR, and determining the purity by HPLC. The method has the advantages of easy availability of raw materials, mild reaction conditions and simple operation, can be used for production in large quantities to meet the needs of use, is a high-efficiency green environmental-protection process and is suitable for industrialized production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry synthesis, in particular to the reaction conditions in a synthesis method of alogliptin benzoate. Background technique [0002] Type 2 diabetes, which refers to adult-onset or non-insulin-dependent diabetes mellitus, is a common disease with an increasing incidence worldwide. According to the latest data released by the International Diabetes Federation (IDF), 97% of people with diabetes in the world currently have type diabetes. Type 2 diabetes is the inability to produce enough insulin due to a poor response to insulin or insulin resistance, and is often associated with obesity, high blood pressure and abnormal lipid levels. As diabetes has become a global health concern, research interest in the condition has increased rapidly. [0003] Inhibitor DPP-4 considered new treatment Therapeutic approach for type 2 diabetes, in a series of compounds of DPP-4 inhibitors, alogliptin benzoate ...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 昌盛马晶杰郑贤静董琳琳尹树铸
Owner JINLIN MEDICAL COLLEGE
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