A kind of process improvement method for preparing Trolagliptin succinate

A technology of trelagliptin succinate and process improvement, applied in the field of preparation of trelagliptin succinate, can solve problems such as being unsuitable for industrialized production, the solvent is not environmentally friendly enough, the process route is complicated and the like, and achieves overcoming cumbersome industrial operation and environmental problems. The effect of less pollution and simplified operation process

Active Publication Date: 2019-04-26
HANGZHOU XINBOSI BIOMEDICAL CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This literature report has the following disadvantages: the process route is relatively complicated, the solvent used is not environmentally friendly, and is not suitable for industrial production

Method used

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  • A kind of process improvement method for preparing Trolagliptin succinate
  • A kind of process improvement method for preparing Trolagliptin succinate
  • A kind of process improvement method for preparing Trolagliptin succinate

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example 1

[0029] Example 1: One-Pot Preparation of Trilagliptin Succinate

[0030] In a 500ml three-necked flask, add 15g of 6-chloro-3-methyluracil, 22.1g of 2-cyano-5-fluorobenzyl bromide and 150ml of ethanol. Add 39.3 g NaHCO with stirring 3 , heated to reflux at 80°C for 3 hours. 24 g of (R)-3-aminopiperidine dihydrochloride was added, and the mixture was refluxed at 80°C for 2 hours. It was cooled to 40°C, 60 ml of dichloromethane was added, and the mixture was stirred for 0.5 hour. Filter, add the filtrate into a 250ml three-necked flask, add 16.6g of succinic acid, and heat under reflux at 80°C for 1 hour. Stirred and cooled overnight, filtered, and the filter cake was dried in a blast drying oven at 60° C. to obtain 28.6 g of off-white crystalline powder (trolagliptin succinate, compound V) with a yield of 64% and a HPLC purity of 99%. see map figure 1 ,Data are as follows:

[0031] 1H NMR(400MHz,dmso)δ8.87(s,3H),7.92(dd,J=8.4,5.6Hz,1H),7.32(t,J=7.6Hz,1H),7.14(d,J=9.0Hz ...

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Abstract

The invention relates to a technological improvement method for preparing trelagliptin succinate (compound V). The method comprises the following steps: by taking 6-chloro-3-methyluracil in formula (I) shown in the description and 2-cyano-5-fluorobenzyl in formula (II) shown in the description as raw materials, carrying out bromo benzyl condensation reaction to obtain a compound III, selecting an appropriate solvent and control reaction condition, enabling a midboy III to be directly subjected to piperidine condensation reaction with (R)-3-aminopiperidine dihydrochloride shown in formula (IV) without separation and purification, and finally carrying out a salifying one-pot method to prepare trelagliptin succinate (compound V). Trelagliptin succinate is prepared by using the one-pot method, so that the reaction steps are reduced, the operation process is simplified, the production efficiency is improved, and the method is safe, environmentally friendly and suitable for the industrialized production.

Description

technical field [0001] The present invention relates to the technical field of preparation method of troglitatin succinate. Background technique [0002] Trelagliptin succinate, chemical name is 2-[6-(3R-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-di Hydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile succinate, developed by Takeda Corporation of Japan, was approved in Japan on March 26, 2015 for the treatment of type 2 diabetes, the first A small molecule diabetes drug that can be administered once a week with good efficacy, no drug resistance and high safety. [0003] There are not many preparation methods of succinate succinate reported in the literature, wherein CN1926128A The preparation method of succinate succinate above is the most commonly used technological method at present, and its route is as follows: [0004] [0005] The process is based on the condensation of 6-chloro-3-methyluracil (compound I) with 2-cyano-5-fluorobenzyl bromide (compound II) in a D...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 杜焕达何永富刘艳华
Owner HANGZHOU XINBOSI BIOMEDICAL CO LTD
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