Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

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
View PDF1 Cites 33 Cited by
  • Summary
  • 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 weak acidity of benzoic acid, under the attack of weakly acidic ions, the oxygen proton of carbamate cannot be cation, unable to lose tert-butyl carbocation, produce carbamic acid, lose CO 2 , and the deprotected amine cannot be obtained, so the Boc cannot be removed smoothly at all, and the final product alogliptin benzoate (I) cannot be obtained
[0024] 4. DMF is used as a solvent, because DMF is highly toxic and not environmentally friendly

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation technique of alogliptin benzoate
  • Preparation technique of alogliptin benzoate
  • Preparation technique of alogliptin benzoate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 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] (III) (VII) (IV)

...

Embodiment 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 product). Add all the...

Embodiment 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). Add all the obta...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
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
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com