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Preparation method for trelagliptin succinate

A technology of troxagliptin succinate and methyl, which is applied in the field of preparation of troxagliptin succinate, can solve problems such as difficult removal of residual solvents, unfavorable industrial production, cumbersome post-processing, etc., and achieves simple and easy production process, Improved purity and yield, and easy post-treatment

Active Publication Date: 2016-09-28
ZHENGZHOU MINGZE MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these methods use high-boiling point solvents, which are troublesome for post-processing and difficult to remove residual solvents; and the reaction time is long and the post-treatment is cumbersome, and because of the cumbersome post-treatment process, the yield is reduced, which is not conducive to industrial production.

Method used

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  • Preparation method for trelagliptin succinate
  • Preparation method for trelagliptin succinate
  • Preparation method for trelagliptin succinate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] The preparation method of trexagliptin succinate comprises the following steps:

[0050] (1) Add 100ml of N-methylpyrrolidone, 25g of 3-methyl-6-chlorouracil, and 21.9g of N,N-diisopropylethylamine in turn to the reaction flask, then stir and dissolve at room temperature; dissolve Afterwards, 2-cyano-5-fluorobenzyl bromide solution was added dropwise to the above mixture at 20°C; after the dropwise addition, the system was heated to 55°C, and the reaction was stopped after 3 hours of reaction; 150ml of Purified water, stirred at -15°C for 1 hour, suction filtered, washed with ethyl acetate three times after the suction filtration, the amount of ethyl acetate each time was 30ml, and then dried in a vacuum oven at 40°C until constant Heavy, obtain 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H) base)methyl]-4-fluorobenzonitrile 44.8g, The yield was 98.0%, and its purity was 98.9% as detected by liquid chromatography, as shown in Figure 1-1 and Figure 1-2;

[...

Embodiment 2

[0059] The preparation method of trexagliptin succinate comprises the following steps:

[0060] (1) Add 280ml of N-methylpyrrolidone, 75g of 3-methyl-6-chlorouracil, and 65.7g of N,N-diisopropylethylamine in turn to the reaction flask, then stir and dissolve at room temperature; Afterwards, 2-cyano-5-fluorobenzyl bromide solution was added dropwise to the above mixture at 40°C; after the dropwise addition, the system was heated to 55°C, and the reaction was stopped after 4 hours of reaction; 480ml of Pure water, stirred at 0°C for 1 hour, suction filtered, washed with isopropanol 3 times with 90ml each time after suction filtration, and then dried to constant weight in a vacuum oven at 40°C to obtain 2- [(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)yl)methyl]-4-fluorobenzonitrile 135.7g, yield 98.9%, Detected by a liquid chromatograph, its purity is 98.9%, as shown in Figure 4-1 and Figure 4-2;

[0061] Wherein said 2-cyano-5-fluorobenzyl bromide solution is a solu...

Embodiment 3

[0069] The preparation method of trexagliptin succinate comprises the following steps:

[0070] (1) Add 220ml of N-methylpyrrolidone, 50g of 3-methyl-6-chlorouracil, and 45.6g of N,N-diisopropylethylamine in turn to the reaction flask, then stir and dissolve at room temperature; After that, add 2-cyano-5-fluorobenzyl bromide solution dropwise to the above mixture at 35°C; after the dropwise addition, raise the temperature of the system to 65°C, stop the reaction after 3.5 hours of reaction; add 300ml of purified water, stirred at 35°C for 1 hour, suction filtered, washed with isopropanol after suction filtration, and then dried to constant weight in a vacuum oven at 30°C to obtain 2-[(6-chloro-3 -Methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)yl)methyl]-4-fluorobenzonitrile 89.6g, the yield was 98.0%, carried out by liquid chromatography Its purity of 98.5% was detected, and the results are shown in Figure 7-1 and Figure 7-2;

[0071] Wherein said 2-cyano-5-fluorobenzyl bromide ...

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Abstract

The invention discloses a preparation method for trelagliptin succinate. The method uses raw materials which are low in toxicity and are small in pollution. The preparation method adopts the following synthesis route as shown in the description. The preparation method is used for preparing the trelagliptin succinate which is relatively high in yield and is relatively high in purity. The preparation method for the trelagliptin succinate is high in safety, is gentle in reaction condition, is high in yield and is high in purity, obviously reduces impurities in a target product, and reduces production cost, and is beneficial for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine preparation, and in particular relates to a preparation method of trexagliptin succinate. technical background [0002] Trexagliptin is a dipeptidyl peptidase IV (DPP-4) inhibitor, which controls blood sugar levels through selective and sustained inhibition of DPP-4. DPP-4 is an enzyme that triggers the inactivation of incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), two incretins in Plays an important role in blood sugar regulation. [0003] Oral DPP-4 inhibitors have gradually attracted widespread attention due to their strong hypoglycemic properties, protection of islet function, and good safety. In March 2015, the world's first once-a-week long-acting oral hypoglycemic drug trelagliptin succinate (trade name Zafatek), jointly developed by Takeda and Furiex, was announced to be approved in Japan for 2 type diabetes treatment. As an ultra-long-acting ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D239/553
CPCC07D239/553C07D401/04
Inventor 郭海波张凤张东阳徐培明
Owner ZHENGZHOU MINGZE MEDICAL TECH
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