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Novel intermediate for synthesizing topirastat and its preparation method

A technology of topirax and intermediates, applied in the field of drug synthesis, can solve the problems of long time, low total yield, unfavorable industrialized large-scale production, etc., and achieve the effects of increased yield, low cost, and easy control of industrialization

Active Publication Date: 2019-01-04
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Because the total yield of this route is low, and the time spent in the first two steps of reaction is longer (for 18 hours), post-processing needs column chromatography, so this route is not conducive to industrialized large-scale production

Method used

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  • Novel intermediate for synthesizing topirastat and its preparation method
  • Novel intermediate for synthesizing topirastat and its preparation method
  • Novel intermediate for synthesizing topirastat and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] The preparation of embodiment one methyl isonicotinate N-oxide compound:

[0033] 1) Put methyl isonicotinate (20g, 145.8mmol) in the reaction flask, add 120ml of acetic acid, stir, then add 30% hydrogen peroxide (16.5g, 145.6mmol) into the reaction flask, heat and stir at 70°C, after 3h , add 30% hydrogen peroxide (11.6g, 102.3mmol), continue to heat and stir, after the reaction is monitored by TLC, concentrate, add 50ml of water, extract with 500ml of dichloromethane, concentrate after drying the organic phase, stir and wash with n-hexane, and filter with suction , a pale yellow crystalline solid was obtained, dried in vacuo at 50° C. to obtain 21.26 g, yield: 95.2%. [M+H] + = 154.03. 1 H NMR (400MHz, CDCl 3 )δ: 3.86-3.91 (s, 3H), 7.78-7.87 (d, 2H), 8.13-8.22 (d, 2H)

[0034] 2) Put methyl isonicotinate (20g, 145.8mmol) in the reaction flask, add 120ml of ethanol, stir, then add 30% hydrogen peroxide (16.5g, 145.6mmol) into the reaction flask, heat and stir at 70°...

Embodiment 2

[0035] The preparation of embodiment diisoniazid N-oxide compound:

[0036] 1) Put methyl isonicotinate N-oxide (20g, 130.6mmol) in the reaction flask, add 200ml of methanol, stir until completely dissolved, then add 85% hydrazine hydrate (14.5g, 246.2mmol) dropwise, nitrogen protection , heated at 60°C for 2h, cooled to room temperature, added 50ml of isopropyl ether and stirred, filtered with suction to obtain an off-white solid, dried in vacuum at 45°C, dry weight 19.3g, yield: 96.5%. [M-H] + = 152.04. 1 H NMR (400 MHz, DMSO) δ: 4.50-4.70 (s, 2H), 7.75-7.82 (d, 2H), 8.26-8.33 (d, 2H), 9.98-10.10 (s, 1H).

[0037] 2) Add methyl isonicotinate N-oxide (2.0g, 13.1mmol) and 20ml of dichloromethane into the reaction flask, stir until completely dissolved, add 85% hydrazine hydrate (1.5g, 25.5mmol) dropwise, and finish , under nitrogen protection, after heating at 40°C for 2h, a large amount of yellow solid precipitated out, stopped heating, cooled to room temperature, and filt...

Embodiment 3

[0038] Example 3 Preparation of 4-(2-(imino(pyridin-4-yl)methyl)hydrazinecarbonyl)pyridine N-oxide:

[0039] 1) Put 4-cyanopyridine (11.0g, 106.0mmol) in a reaction flask, add 150ml of methanol, stir until completely dissolved, add 55mg of sodium methoxide, protect with nitrogen, heat at 40°C, react for 2 hours, then add isoniazid N-oxide (15.0g, 98.0mmol), reacted for 3h, cooled to room temperature, added isopropyl ether (90ml) into the bottle, stirred, and filtered with suction to obtain a yellow powdery solid, vacuum-dried at 50°C, dry weight 24.4g , Yield: 96.8%. [M+H] + = 258.10. 1 H NMR (400MHz, DMSO) δ: 6.87-7.13(br, 2H), 7.75-7.83(d, 2H), 7.88-7.93(d, 2H), 8.28-8.36(d, 2H), 8.62-8.71(d , 2H), 9.98-10.70 (br, 1H).

[0040] 2) Put 4-cyanopyridine (11.0g, 106.0mmol) in the reaction flask, add 150ml of ethanol, stir until completely dissolved, add sodium ethoxide (60mg), protect with nitrogen, heat at 40°C, react for 2 hours, add iso Niacinazine N-oxide (15.0g, 98.0mmol...

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Abstract

The present invention provides a new topiroxostat synthesis intermediate 4-(2-(imino(pyridine-4-yl)methyl)hydrazinocarbonyl)pyridine N-oxide (compound VI) and a preparation method thereof, wherein isoniazid N-oxide IV and 4-cyanopyridine V are subjected to a reaction in a suitable solvent under an alcohol alkali condition to obtain the product, the alcohol alkali is selected from sodium methoxide, sodium ethoxide, potassium ethoxide or potassium t-butoxide, and the reaction formula is defined in the specification. According to the present invention, through the compound VI, the gout treating drug topiroxostat can be prepared under the mild and easy industrial control reaction conditions.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a new intermediate for synthesizing the drug topirastat for the treatment of gout, 4-(2-(imino(pyridin-4-yl)methyl)hydrazinecarbonyl)pyridine N-oxide , and a preparation method thereof. Background technique [0002] Topiroxostat (Topiroxostat), the chemical name is 5-(2-cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole, which is produced by Japan Fuji Pharmaceutical Co., Ltd. A new molecular entity drug developed and launched in Japan for the first time in August 2013. Its trade name is For the treatment of gout, hyperuricemia. [0003] Chinese patent CN 1561340 discloses a method and route for synthesizing topirastat, see route 1 for details: [0004] [0005] This patent route (shown in Route 1) uses isonicotinic acid N-oxide as a raw material, and in the presence of 2-ethoxyl-1-ethoxycarbonyl-1,2-dihydroquinoline (abbreviated as EEDQ) and methanol Esterification t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/89C07D401/14
Inventor 张涛韩强郭晔堃钟静芬
Owner SHANGHAI INST OF PHARMA IND CO LTD
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