Preparation technique of alogliptin benzoate

A preparation process, the technology of benzoic acid, which is applied in the field of medicine, can solve the problems of unobtainable, difficult to obtain, low purity, etc., and achieve the effects of reduced process, reduced dosage and high yield

Inactive Publication Date: 2013-02-27
成都天翼医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] 1. The raw material 1-(2-isocyanobenzyl)-3-methylurea (Ⅴ) is not easy to obtain
[0022] 2. Hydrolysis with NaOH solution is easy to destroy the product, and the obtained intermediate 2-(6-chloro-3methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1- Methyl)-benzonitrile (Ⅲ) has a low purity
[0023] 3. Finally, use benzoic acid to directly remove Boc from the compound (VII) protected by tert-butoxycarbonyl group to obtain benzoate. Due to the we

Method used

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  • Preparation technique of alogliptin benzoate
  • Preparation technique of alogliptin benzoate
  • Preparation technique of alogliptin benzoate

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0052] Example 1

[0053] Step 1: Preparation of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile

[0054]

[0055] (II) (III)

[0056] Add 6-chloro-3-methyluracil (80.3g, 0.5mol) and 2-cyanobenzyl bromide (107.8g, 0.55mol) into the reaction flask, add toluene 400ml, tri-n-butylamine (139g, 0.75 mol), stirred and heated to 80°C, and reacted for 5 hours. Heating was stopped, the temperature of the system was lowered to room temperature, 250 ml of purified water was added to the system, stirred for 30 minutes, filtered under reduced pressure, the filter cake was rinsed with 150 ml of purified water and then sucked dry to obtain 121 g of off-white color. Yield: 87.78%, content: 97.2%.

[0057] The 6-chloro-3-methyluracil was purchased from: Nanjing Kangmanlin Industrial Co., Ltd.

[0058] Second step: Preparation of (R)-2-[(6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1( 2H)-yl)methyl]benzonitrile

[0059]

[0060]...

Example Embodiment

[0066] Example 2

[0067] Basically the same as embodiment 1, on this basis:

[0068] Second step: Preparation of (R)-2-[(6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1( 2H)-yl)methyl]benzonitrile

[0069] 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile (110.3 g, 0.4 mol) and ( R)-3-Boc-aminopiperidine (88.1g, 0.44mol) was added to the reaction flask, 600ml of absolute ethanol and potassium carbonate (110.4g, 0.8mol) were added, stirred and heated to reflux, and refluxed for 10 hours. Potassium carbonate was removed by filtration under reduced pressure, and the filtrate was transferred to a reaction flask, p-toluenesulfonic acid (172.2 g, 1.0 mol) was slowly added, stirred and heated to reflux, and refluxed for 3 hours, a large amount of solids precipitated out of the reaction system. Filter under reduced pressure, and rinse the filter cake with 100 ml of absolute ethanol. Drained to obtain 172 g of white solid (wet pr...

Example Embodiment

[0070] Example 3

[0071] Basically the same as embodiment 1, on this basis:

[0072] Second step: Preparation of (R)-2-[(6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1( 2H)-yl)methyl]benzonitrile

[0073] 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile (110 g, 0.4 mol) and (R )-3-Boc-aminopiperidine (88g, 0.44mol) was added to the reaction flask, 600ml of absolute ethanol and potassium carbonate (55.2g, 0.4mol) were added, stirred and heated to reflux, and refluxed for 10 hours. Potassium carbonate was removed by filtration under reduced pressure, and the filtrate was transferred to a reaction flask, p-toluenesulfonic acid (103.3 g, 0.6 mol) was slowly added, stirred and heated to reflux, and refluxed for 3 hours, a large amount of solids precipitated out of the reaction system. Filter under reduced pressure, and rinse the filter cake with 100 ml of absolute ethanol. Drained to obtain 162 g of white solid (wet product...

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Abstract

The invention relates to a preparation technique of a medicine alogliptin benzoate for treating Type 2 diabetes. The technique comprises the following steps: reacting the raw material 6-chloro-3-methyluracil with 2-cyanobenzyl bromide to prepare 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidyl-ylmethyl)-benzonitrile, and carrying out substitution reaction with (R)-3-Boc-aminopiperidine; after the reaction finishes, removing Boc to obtain alogliptin; and finally, salifying with benzoic acid to obtain the alogliptin benzoate. The invention is characterized in that in the substitution reaction, the acid binding agent potassium carbonate is added; and after the reaction finishes, filtration is carried out, and p-toluenesulfonic acid is added into the filtrate to remove the Boc. The preparation technique provided by the invention has the advantages of simple procedure, higher product yield and higher product purity.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a drug alogliptin benzoate for the treatment of type 2 diabetes: (R)-2-[(6-(3-aminopiperidin-1-yl)-3-methyl - Preparation process of 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]benzonitrile benzoic acid. Background technique [0002] Type 2 diabetes is a syndrome characterized by hyperglycemia caused by impaired stable control of glucose metabolism itself, accounting for about 90% of all diabetes cases. Oral hypoglycemic drugs commonly used in clinical practice mainly include biguanides, sulfonylureas, thiazolidinediones, meglitinides, and α-glucosidase inhibitors. In recent years, with the in-depth study of the pathophysiological mechanism of type 2 diabetes, the research and development of new oral hypoglycemic drugs has provided more and better treatment options for the treatment of type 2 diabetes. [0003] Alogliptin Benzoate (Ⅰ), chemical name: (R)-2-[(6-(3-aminop...

Claims

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Application Information

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IPC IPC(8): C07D401/04
Inventor 崔翼罗邻涛周定康刘三勇
Owner 成都天翼医药科技有限公司
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