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Preparation method of trelagliptin succinate

A technology of troxagliptin succinate and intermediates, applied in the field of pharmaceutical production, can solve the problems of poor economic benefits and high production costs

Active Publication Date: 2020-04-03
JIANGSU TIANHE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The current production cost of this method is high, and the economic benefit is poor

Method used

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  • Preparation method of trelagliptin succinate
  • Preparation method of trelagliptin succinate
  • Preparation method of trelagliptin succinate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Add 300g of toluene and 75g of 3-aminopiperidine into a 500mL four-necked reaction flask, add 83.5g of benzaldehyde under stirring, then raise the temperature and reflux with water until no water comes out, and the temperature of the material liquid reaches above 110°C. Bring to room temperature, filter, wash the filter cake with an appropriate amount of drinking water, and filter to dry to obtain intermediate III. After drying, 136.5 g of intermediate III is obtained as a dry product.

[0033] Add 600g of DMF, 150g of II, and 141g of anhydrous potassium carbonate to a 1L four-necked reaction flask, raise the temperature to 60-70°C, put in 96g of intermediate III, then keep it warm for 8 hours, and filter at room temperature. Distill DMF to dryness under pressure to obtain a reddish-brown oily substance, which is the condensation intermediate IV.

[0034] Then add 900ml of drinking water, after stirring, convert it into a 2L four-necked reaction flask, add 186g of hydro...

Embodiment 2

[0043] Add 300g of toluene and 50g of 3-aminopiperidine into a 500mL four-necked reaction flask, add 63.6g of benzaldehyde under stirring, then heat up and reflux with water until no water comes out, and the temperature of the material liquid reaches above 110°C. Bring to room temperature, filter, wash the filter cake with an appropriate amount of drinking water, and filter to dry to obtain intermediate III. After drying, 88.9g of intermediate III is obtained as a dry product.

[0044] Add 480g of DMF, 80g of intermediate II, and 83g of anhydrous potassium carbonate to a 1L four-necked reaction flask, raise the temperature to 60-70°C, put in 51.3g of intermediate III, keep it warm for 4 hours, and filter it at room temperature. DMF was distilled under reduced pressure in the reaction flask to dryness, then 900ml of drinking water was added, and after stirring, it was converted into a 2L four-necked reaction flask, and 166g of hydrochloric acid with a mass content of 30% was add...

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Abstract

The invention relates to a preparation method of trelagliptin succinate in the technical field of medicine production. The preparation method comprises the following steps of: taking 2-[(6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydropyrimidine-1(2H)-yl)methyl]-4-fluorobenzonitrile (II) and 3-aminopiperidine (I) as initial raw materials, reacting 3-aminopiperidine with benzaldehyde to generate N-benzylidene piperidine-3-amine (III), protecting a primary amino group, condensing the produced III with II to produce a condensation compound (IV), performing acidolysis on the condensation compound (IV) under an acidic condition to remove a protecting group to obtain a trelagliptin crude product (V), and finally, salifying V with succinic acid to obtain trelagliptin succinate (VI). The raw materials selected by adopting the synthesis method are cheap and easily available, benzaldehyde can be recycled, the loss is small, the material cost is low, and the preparation method of trelagliptin succinateis a new synthesis method.

Description

technical field [0001] The invention relates to a preparation method of a drug for controlling blood sugar, in particular to a preparation method of trexagliptin succinate, which belongs to the technical field of pharmaceutical production. Background technique [0002] The chemical name of trelagliptin succinate is 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro -2H-pyrimidin-1-ylmethyl]-4-fluorobenzonitrile succinate is a dipeptidyl peptidase IV (DPP-IV) inhibitor developed by Takeda Pharmaceutical Co., Ltd., through selectivity, Sustained inhibition of DPP-4 to control blood sugar levels. Trexagliptin has good safety and tolerability, once a week administration can effectively control the blood sugar level and improve the medication compliance of patients, the drug has a broad market prospect. [0003] At present, there are 2 synthetic routes for trexagliptin: ① Use 2-bromo-5-fluorotoluene (2) as the starting material, dimethylformamide (DMF) as the solvent,...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07C55/10C07C51/41
CPCC07D401/04Y02P20/55
Inventor 刘磊赵云德朱林飞魏莉周杰陈浩
Owner JIANGSU TIANHE PHARMA CO LTD
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