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Synthesis process of trelagliptin succinate

A technology for the synthesis process of troxagliptin succinate, which is applied in the field of synthesis process of troxagliptin succinate, can solve the problems of low total yield and achieve the effect of increasing yield and improving the total yield

Pending Publication Date: 2021-06-11
HEFEI UNIV OF TECH
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  • Description
  • Claims
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Problems solved by technology

[0004] Patent CN 105968093A discloses a preparation method of trexagliptin succinate, using 3-methyl-6-chlorouracil, 2-cyano-5-fluorobenzyl bromide, (R)-3-aminopiperidine Dihydrochloride and succinic acid are used as reaction raw materials, and succinate trexagliptin is obtained through three-step reaction, although the purity of its prepared intermediate and product are all higher, the overall yield is lower, its embodiment 1, The total yield of embodiment 2, embodiment 3 is respectively 60.5%, 65.4%, 60.3%, so the improvement of total yield is the key of the synthetic technique research of trexagliptin succinate

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  • Synthesis process of trelagliptin succinate
  • Synthesis process of trelagliptin succinate

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Experimental program
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Embodiment 1

[0028] (1) Preparation of intermediate 1: 2-cyano-5-fluorobenzyl bromide (21.40 g, 0.1 mol) and 6-chloro-3-methyluracil (16.86 g, 0.105 mol) were added to 250 mL of tetrahydrofuran, Heat to 30°C and stir for 15 minutes, then add 1.07g of cuprous acetylacetonate and potassium carbonate (14.51g, 0.105mol), heat to 60°C for 3 hours, stop the reaction, add water to the reaction system and stir, filter, filter cake with petroleum ether After washing and drying, Intermediate 1 was obtained with a yield of 98.21% and an HPLC purity of 99.21%.

[0029] (2) Preparation of Intermediate 2: Add Intermediate 1 (29.37g, 0.1mol), 1.47g dibutyltin dichloride and triethylamine (10.62g, 0.105mol) to 250mL isopropanol, and stir at room temperature 15min, then add (R)-3-aminopiperidine dihydrochloride (18.17g, 0.105mol), heat to 60°C for 5h, stop the reaction, add water to the reaction system and stir, filter, filter cake with petroleum ether Wash, recrystallize with ethyl acetate-petroleum ethe...

Embodiment 2

[0032] (1) Preparation of intermediate 1: 2-cyano-5-fluorobenzyl bromide (21.40 g, 0.1 mol) and 6-chloro-3-methyluracil (16.86 g, 0.105 mol) were added to 250 mL of tetrahydrofuran, Heat to 40°C and stir for 15 minutes, then add 1.28g of cuprous acetylacetonate and sodium bicarbonate (8.82g, 0.105mol), heat to 60°C for 3 hours, stop the reaction, add water to the reaction system and stir, filter, filter cake with petroleum After washing with ether and drying, intermediate 1 was obtained with a yield of 98.93% and a purity of 99.23% by HPLC.

[0033] (2) Preparation of Intermediate 2: Add Intermediate 1 (29.37g, 0.1mol), 1.47g dibutyltin dichloride and triethylamine (10.62g, 0.105mol) to 250mL isopropanol, and stir at room temperature 15min, then add (R)-3-aminopiperidine dihydrochloride (18.17g, 0.105mol), heat to 65°C for 5h, stop the reaction, add water to the reaction system and stir, filter, filter cake with petroleum ether Wash, recrystallize with ethyl acetate-petroleum...

Embodiment 3

[0036] (1) Preparation of intermediate 1: 2-cyano-5-fluorobenzyl bromide (21.40 g, 0.1 mol) and 6-chloro-3-methyluracil (16.54 g, 0.103 mol) were added to 250 mL of tetrahydrofuran, Heat to 40°C and stir for 15 minutes, then add 1.07g of cuprous acetylacetonate and sodium carbonate (10.92g, 0.103mol), heat to 70°C for 3 hours, stop the reaction, add water to the reaction system and stir, filter, filter cake with petroleum ether After washing and drying, Intermediate 1 was obtained with a yield of 98.37% and an HPLC purity of 99.25%.

[0037](2) Preparation of Intermediate 2: Add Intermediate 1 (29.37g, 0.1mol), 1.76g of dibutyltin dichloride and triethylamine (10.62g, 0.105mol) to 250mL of isopropanol, and stir at room temperature 15min, then add (R)-3-aminopiperidine dihydrochloride (18.17g, 0.105mol), heat to 70°C for 5h, stop the reaction, add water to the reaction system and stir, filter, filter cake with petroleum ether Wash, recrystallize with ethyl acetate-petroleum et...

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Abstract

The present invention discloses a trelagliptin succinate synthesis process, and relates to the technical field of pharmaceutical chemical synthesis. In the process, 2-cyano-5-fluorobenzyl bromide and 6-chloro-3-methyl uracil are adopted as starting raw materials, and condensation reaction is performed under the action of cuprous acetylacetonate and an acid-binding agent I to prepare an intermediate 1; then the intermediate 1 and (R)-3-aminopiperidine dihydrochloride are subjected to a condensation reaction under the action of dibutyltin dichloride and an acid-binding agent II to prepare an intermediate 2, and the intermediate 2 and succinic acid are subjected to a salt forming reaction to prepare trelagliptin succinate. Herein, the acid-binding agent and the catalyst are matched to improve the yield of the intermediate 1 and the intermediate 2, so that the total yield of the trelagliptin succinate is improved, the total yield reaches 80% or above, and the purity of the trelagliptin succinate reaches 99.5% or above.

Description

Technical field: [0001] The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a synthesis process of trexagliptin succinate. Background technique: [0002] The drugs currently used clinically to treat type 2 diabetes mainly include oral hypoglycemic drugs and insulin. Among them, oral hypoglycemic drugs are mainly divided into 6 categories: sulfonylureas, glinides, metformin, glycosidase inhibitors, insulin sensitizers and DPP-4 inhibitors. Among them, DPP-4 is an enzyme that can trigger the inactivation of incretin (glucagon-like peptide-1, GLP-1) and glucose-dependent insulinotropic polypeptide, GIP), and these two incretins Plays an important role in blood sugar regulation. Therefore, inhibition of DPP-4 can increase blood glucose level-dependent insulin secretion, thereby controlling blood glucose levels. [0003] Trelagliptin succinate, developed by Takeda and Furiex, was launched in Japan on March 7, 2015 under the trade...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07C51/41C07C55/10
CPCC07D401/04C07C51/412C07C55/10Y02P20/55
Inventor 李青山方梦圆阮班锋
Owner HEFEI UNIV OF TECH
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