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Methods for the preparation of topiroxostat and intermediates thereof

A technology for the application of topicastat, which is applied in the direction of medical preparations containing active ingredients, pharmaceutical formulas, urinary system diseases, etc., and can solve problems such as expensive starting materials and low yields

Inactive Publication Date: 2018-01-02
PHARMATHEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On the other hand, CN103724329B - consisting of many steps - uses expensive starting materials and suffers from low yield
In addition, it employs the use of cyanuric chloride, which is a toxic reagent

Method used

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  • Methods for the preparation of topiroxostat and intermediates thereof
  • Methods for the preparation of topiroxostat and intermediates thereof
  • Methods for the preparation of topiroxostat and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Preparation of 2-carbamoyl-4-cyano-pyridine 3a

[0079] 100 g of 4-cyano-pyridine followed by 800 ml of acetonitrile was added to a 3 L 4 neck round bottom flask equipped with a magnetic stirrer, thermometer and 500 mL addition funnel. Sulfuric acid (20ml) was added dropwise at room temperature. The resulting suspension was heated at 60°C. 60 ml of formamide solution (200 ml) in demineralized water (D.M. water) was charged to the addition funnel and added over a period of 10 min at 60°C. The resulting clear solution was heated at 70°C. 328 g of ammonium peroxodisulfate were added portionwise to the solution, maintaining a temperature between 70-75°C. After the addition was complete, the reaction mixture was stirred at 75°C for about 1 hour. The reaction was monitored by TLC and upon completion, 1 L of demineralized water was added. The solvent was distilled off under vacuum. The warm suspension was filtered off. The wet cake was rinsed with 500 mL of demineralize...

Embodiment 2

[0082] Preparation of 4-(5-(pyridin-4-yl)-1 H-1,2,4-triazol-3-yl)pyridineamide 7

[0083] 115 g of 2-carbamoyl-4-cyano-pyridine (3a), followed by 1150 mL of methanol were added to a 2 L hydrogenator equipped with a magnetic bar. 26.6 g of sodium methoxide were added portionwise at room temperature. The suspension was left under stirring for 2 hours to form the corresponding imino ether. After consumption of the starting material, 106.9 g of isoniazid (5b) were added. The resulting suspension was heated at 90° C. for 2 hours under pressure (4 bar). The reaction was heated at 100° C. for 6-10 hours with stirring and under pressure (4 bar). The suspension was filtered off, the wet cake was rinsed with 200 ml of methanol and dried under vacuum to afford 121 g of 4-(5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl)pyridineamide 7.

[0084] The filtrate was evaporated to dryness to afford 185 g of crude product. The crude product was dissolved in 555 ml demineralized water. The resulti...

Embodiment 3

[0087] Preparation of topinostat

[0088]10.0 g of 4-(5-(pyridin-4-yl)-lH-l,2,4-triazol-3-yl)pyridineamide (7) dissolved in 60 ml of THF was added to a device equipped with a magnetic stick and thermometer 250ml 3 neck round bottom flask. 7.86 ml of triethylamine were added. The reaction mixture was cooled at 0 °C and 6.95 ml trifluoroacetic anhydride (TFAA) was added dropwise. After addition of TFAA, the reaction mixture was left to stir at room temperature. The reaction was monitored by TLC and upon completion the solvent was evaporated and the crude API TFA salt was isolated as a yellow solid. The salt was dissolved in 50 ml MeOH and heated at 70 °C for 1 h. The suspension was cooled at room temperature and filtered off. The wet cake was rinsed with 200 ml of refrigerated methanol and dried under vacuum to provide 7.6 g of 4-(5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl)pyridine-2- Picolinitrile TFA salt.

[0089] 1H-NMR (500MHz, DMSO) δ8.94(d, 1H), 8.89(d, 2H), 8.54(s, 1H...

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Abstract

The present invention relates to novel preparation methods for Topiroxostat through novel intermediates comprising novel methods for the formation of the triazole ring and for cyanation of the pyridylring.

Description

technical field [0001] The present invention relates to a novel preparation method for Topiroxostat through novel intermediates. Background technique [0002] Topinastat of formula 1 belongs to a large family of novel 1,2,4-triazole compounds and is characterized by a high xanthine oxidase inhibitory activity. It is also useful as a therapeutic agent for hyperuricemia and gout, which is hyperuricemia due to increased production of uric acid. Topicastat showed effective reduction of serum urate levels in hyperuricemic patients with and without gout. [0003] Topicastat or FYX-051 was first developed by Fuji Yakuhin Co. Ltd. and its synthesis is described in EP1471065B. In this first synthesis of topinastat 1, the introduction of the cyano group on the pyridine ring occurred in the first step before the condensation reaction. [0004] [0005] Several years later, a new process for the preparation of topicastat of formula 1 was disclosed. The new method described in EP1...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61K31/4439A61P13/00
CPCA61P13/00C07D401/14
Inventor V·T·卡夫提斯E·尼尔科斯米蒂斯T·安德烈乌C·斯泰撒基斯P·格卡兹赛尔
Owner PHARMATHEN
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