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Preparation method of trelagliptin succinate

A technology of trelagliptin succinate and succinic acid, applied in the field of preparation of trelagliptin succinate, can solve problems such as unfavorable intermediate MI purification, failure to effectively control isomer impurities, unfavorable amplification of production and the like

Inactive Publication Date: 2020-06-30
ZHEJIANG WAN SHENG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But this route still has shortcoming: used high boiling point solvent in the reaction process of 2-cyano-5-fluorobenzyl bromide and 6-chloro-3-methyluracil, is unfavorable for post-reaction treatment and purification of product intermediate MI; And the isomer impurity produced by the reaction of intermediate MI and (R)-3-aminopiperidine dihydrochloride can not be effectively controlled, which is not conducive to the scale-up production

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

[0045] Embodiment 1: the preparation of intermediate MI

[0046]

[0047]Add toluene into the 200L reactor, start stirring, and add 16.0kg of 6-chloro-3-methyluracil, 23.5kg of 2-cyano-5-fluorobenzyl bromide and 27.7kg of tri-n-butylamine in sequence. Under stirring, raise the temperature of the mixture to 80±5°C, keep the reaction at this temperature for about 6 hours, monitor the reaction by TLC (petroleum ether: ethyl acetate = 3:2), when 6-chloro-3-methyluracil is basically consumed Completely both as the end point of the reaction.

[0048] After the reaction is complete, add 48.0L of purified water to the reaction kettle, cool down to 20±5°C, stir for 0.5h to 1h, centrifuge, wash the filter cake twice with purified water (24.0L×2), centrifuge, and collect the filter cake , transfer the filter cake to a 200L reaction kettle, add 64.0L of isopropanol, beat at room temperature for 1 to 2 hours, centrifuge, and stir the filter cake twice with isopropanol (16.0L×2), collec...

Embodiment 2

[0053] Embodiment 2: the preparation of intermediate MII

[0054]

[0055] Add 260.0L of isopropanol and 36.4L of purified water into the 800L reactor, start stirring, and then add 26.0kg of intermediate MI, 22.9kg of (R)-3-aminopiperidine dihydrochloride and 32.8kg of anhydrous sodium carbonate . The mixture was heated to 70±5°C under stirring, and kept at this temperature for about 18 hours. The reaction was monitored by TLC (dichloromethane:methanol=20:1), and the end point of the reaction was when the intermediate MI was basically completely consumed.

[0056] After the reaction is complete, add 260.0 L of ethyl acetate into the reaction kettle, cool down to 20±5°C, stir for 0.5-1 h, centrifuge, collect the filtrate, and filter cake for later use. Add the filtrate into an 800L reaction kettle, slowly add an appropriate amount of concentrated hydrochloric acid under stirring, adjust the pH to 3-5, and precipitate a solid. Stir for 0.5h and centrifuge to collect the sol...

Embodiment 3

[0063] Embodiment 3: the preparation of trexagliptin succinate

[0064]

[0065] Add 102.5L of absolute ethanol to the 200L reactor, and add 20.5kg of intermediate MII under stirring. Raise the temperature to 80±5°C to dissolve it, inject it into a 500L reactor in the clean area while it is hot, and keep stirring at 80±5°C; add 102.5L of absolute ethanol to another 200L reactor, and add 7.18kg of succinic acid while stirring. Raise the temperature to 80±5°C to dissolve it, and slowly inject it into a 500L reactor in the clean area while it is still hot. Solids will precipitate during the addition process. After the addition is complete, keep warm at 80±5°C for 6 hours. Then lower the temperature to 20±5°C, stir for 1-2h, centrifuge, stir and wash the filter cake with 41.0L of absolute ethanol, centrifuge, collect the filter cake, and vacuum-dry at 50±5°C to obtain the finished product of Trexagliptin succinate ( 26.20kg, yield: 96%, purity: 99.9%).

[0066] 1 H NMR (500M...

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Abstract

The invention provides an improved preparation method of trelagliptin succinate. The method comprises the following steps: by using 6-chloro-3-methyluracil and 2-cyano-5-fluorobenzyl bromide as initial raw materials, carrying out substitution reaction twice, refining, and carrying out a salifying reaction to obtain the trelagliptin succinate finished product. The method has the advantages of simple process, easily available raw materials, economy, environmental protection, high product yield, purity of 99% or above, and facilitation of realization of industrialization.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a preparation method of trexagliptin succinate, a medicine for treating type II diabetes. Background technique [0002] Diabetes mellitus (Diabetes Mellitus) is a chronic comprehensive disease mainly caused by the disorder of glucose metabolism caused by absolute or relative insulin deficiency or decreased sensitivity of target cells to insulin, which seriously affects the health and quality of life of patients. Drug therapy is still the main method for the treatment of type 2 diabetes, and the number of type 2 diabetes patients in China ranks first in the world. [0003] DPP-4 inhibitors are a new class of oral hypoglycemic drugs that do not cause common side effects of traditional hypoglycemic drugs such as hypoglycemia, weight gain, and cardiovascular side effects. The advantages are obvious. The DPP-4 inhibitors currently on the market in China basically requi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07C51/41C07C55/10
CPCC07D401/04
Inventor 何俊马猛单瑞平叶锐沈珉霁
Owner ZHEJIANG WAN SHENG PHARMA CO LTD
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