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Topiroxostat and preparation method of intermediate of topiroxostat

A technology for an intermediate and topiramate, which is applied in the field of preparation of topiramate and its intermediates, can solve problems such as environmental protection problems and potential safety hazards, and achieve the effects of good industrial prospects, high yield and high product quality.

Inactive Publication Date: 2018-06-01
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In the above method, highly toxic cyanides such as sodium cyanide, potassium cyanide, zinc cyanide, and trimethylsilyl cyanide are used, and there are environmental problems and potential safety hazards.

Method used

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  • Topiroxostat and preparation method of intermediate of topiroxostat
  • Topiroxostat and preparation method of intermediate of topiroxostat
  • Topiroxostat and preparation method of intermediate of topiroxostat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment one, the synthesis of 4-pyridine carboximidic acid hydrazine

[0034]

[0035] Add 2.08kg of 4-cyanopyridine to a 20L reactor, add 10L of ethanol and 8.8g of sodium methoxide, raise the temperature to 40°C and stir for 9 hours, TLC detects that the basic reaction of the raw materials is complete; take another 20L reactor, add 5L of ethanol, 1.41kg 85% hydrazine hydrate and 12ml concentrated hydrochloric acid, pour the reaction solution from the previous step slowly, stir at room temperature for 1h, and TLC detects that the reaction of the raw materials is complete; 35°C rotary evaporation removes most of the solvent to a semi-oily solid, add 15L methyl The tert-butyl ether was stirred at room temperature, filtered, and vacuum-dried at 30° C. to obtain 2.31 kg of light yellow intermediate III, with a yield of 84.9%, and HPLC of 98%. [M+H] + = 137.2. 1 H NMR (400MHz, DMSO) δ: 8.50-8.52(d,2H), 7.63-7.65(d,2H), 5.74(br,2H), 5.40(br,2H).

Embodiment 2

[0036] Example two, the synthesis of 4-pyridinecarbohydrazide-N'-(2-cyanopyridine-4-carbonimido)

[0037]

[0038] Add 847g of compound IIB to a 20L reaction kettle, add 4.5L of DMF, then add 1.64Kg EDC·HCl and 1.14Kg HOBT, stir at room temperature to dissolve, then add 934g of intermediate III, stir at room temperature for 12h, TLC detection of raw materials The reaction was complete; 4.5 L of dissolved 719 g of sodium bicarbonate aqueous solution and 9 L of ethyl acetate were added, stirred at room temperature for 12 h, a large number of yellow solids precipitated, filtered, and air-dried at 50 ° C to obtain 1.38 kg of light yellow solid, yield 91.3%, HPLC 99.3 %. [M+H] + = 267.2. 1 H NMR (400MHz, MeOD) δ: 8.83-8.85(d,1H), 8.70-8.72(d,2H), 8.45(d,1H), 8.16-8.18(dd,1H), 7.87-7.89(dd,2H ).

Embodiment 3

[0039] Example three, the synthesis of 4-pyridinecarbohydrazide-N'-(2-cyanopyridine-4-carbonimido)

[0040]

[0041] Add 847g IIB to a 20L reaction kettle, add 4.5L DMF, then add 0.94Kg DIC and 1.14Kg HOBT, stir at room temperature to dissolve, then add 934g of intermediate III, stir at room temperature for 12 hours, and TLC detects that the raw materials have reacted completely; Add 4.5 L of water and 9 L of ethyl acetate, stir at room temperature for 2 h, a large amount of yellow solid precipitates, filter, and air-dry at 50°C to obtain 1.43 kg of light yellow solid, yield 94.7%, HPLC 99.0%. [M+H] + = 267.2. 1 H NMR (400MHz, MeOD) δ: 8.83-8.85(d,1H), 8.70-8.72(d,2H), 8.45(d,1H), 8.16-8.18(dd,1H), 7.87-7.89(dd,2H ).

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Abstract

4-cyanopyridine is taken as a raw material, a compound III is obtained through a reaction, the compound III and a compound IIB undergo an amidation reaction to obtain a compound IV, and a ring-closurereaction is carried out in the function of an acid catalyst to obtain a target topiroxostat molecule. According to the scheme, the raw materials are cheap and are easy to obtain, the product qualityis high, the reaction is simple to operate and is mild, the yield is high, and the waste gas, waste water and industrial residue are less produced. In the reaction process, nitrogen protection isn't required, and a cyaniding reagent isn't used, so that the method has bright industrial prospects.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of topirastat and its intermediate. Background technique [0002] Topirastat, chemical name: 4-[5-(pyridin-4-yl)-1H-[1,2,4]triazol-3-yl]pyridine-2-carbonitrile, English name: Topiroxostat, commodity Name: TOPILORIC, is a non-purine xanthine oxidoreductase selective inhibitor for the treatment of gout, hyperuricemia. The chemical structure is as follows: [0003] [0004] The patent CN104411686 applied by Japan Co., Ltd. Fuji Pharmaceutical in China discloses a preparation method of topirastat: [0005] [0006] The method adopts the reaction of compound (2) and isoniazid in the presence of alkali metal alkoxide to obtain compound (3), the cyanation reaction in the presence of a cyanating agent to obtain compound (4), and then ring closure under the action of an acid catalyst The reaction yields the target molecule. [0007] The patent ...

Claims

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Application Information

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IPC IPC(8): C07D213/86C07D401/14
CPCC07D213/86C07D401/14
Inventor 张孝清宋志春包金远翟洪
Owner NANJING HUAWE MEDICINE TECH DEV
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