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Preparation method of topiroxostat

A kind of topicastat, intermediate technology

Inactive Publication Date: 2020-10-09
孙哲
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] The route is short and the steps are simple, but one of the starting materials, 4-cyanopyridine nitrogen oxide, is expensive and the supply in the market is small; the second step requires a large excess of cyanide zinc cyanide (3.0 eq) , and the yield is not high, about 66%, and it has great environmental pollution

Method used

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  • Preparation method of topiroxostat
  • Preparation method of topiroxostat
  • Preparation method of topiroxostat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1, the preparation method of intermediate 1:

[0038]

[0039] The starting material (20.0 g, 0.16 mol, 1.0 eq) was dissolved in acetic acid (100 mL) at room temperature (about 25 o C) Add hydrogen peroxide (54.4 g, content 30%, 0.48 mol, 3.0 eq), heat up to 90 o C reacted for 8 h. HPLC showed that there was no raw material left, stop heating, lower to room temperature, add 200 mL of acetone, crystallize for 1 h, filter, and rinse the filter cake twice with a small amount of acetone (100 mL in total). The resulting solid was at 45 o C under blast drying for 10 h. 20.91 g of the product was obtained, yield: 93.9%.

Embodiment 2

[0040] Embodiment 2, the preparation method of intermediate 2:

[0041]

[0042] Intermediate 1 (10.0 g, 71.9 mmol, 1.0 eq) was dissolved in methanol (80 mL), concentrated sulfuric acid (5.0 g) was added dropwise, and the internal temperature was controlled not to exceed 40 o C, heat up to an external temperature of 75 o C, reflux reaction for 8 h. TLC showed that there were not many remaining raw materials, so stop heating, cool down in an ice-water bath, add solid sodium carbonate in batches, and control the internal temperature not to exceed 20 o C, adjust the pH to about 7, filter, and rinse the filter cake twice with a small amount of methanol. methanol at 45 o C and evaporated to dryness under reduced pressure, the obtained solid was dissolved in dichloromethane (100 mL), and washed once with 5% aqueous sodium carbonate solution (15 mL). The dichloromethane phase was separated, dried with a little sodium sulfate, at 45 o C and evaporated to dryness under reduced ...

Embodiment 3

[0043] Embodiment 3, the preparation method of intermediate 3:

[0044]

[0045] Intermediate 2 (12.0 g, 78.4 mmol, 1.0 eq) was added to methanol (80 mL), hydrazine hydrate (80% content, 5.88 g, 94.0 mmol, 1.2 eq) was added, and the temperature was raised to 70 o C, reflux reaction for 6 h. TLC showed that the raw material was completely consumed, and the ice-salt bath was cooled to an internal temperature of 5 o Within C, crystallize for 2 h, filter, and rinse the filter cake with a small amount of methanol (20 mL). The resulting solid was at 45 o C under air blast drying for 4 h to obtain 11.09 g of the product with a yield of 92.4%.

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Abstract

The invention provides a preparation method of topiroxostat. The method comprises the following steps: subjecting isonicotinic acid as a starting material to oxidation with hydrogen peroxide to obtainisonicotinic acid-nitric oxide (an intermediate 1); then esterifying with methanol to obtain methyl isonicotinate-nitric oxide (intermediate 2); then performing hydrazinolysis with hydrazine hydrateto obtain isoniazide-nitric oxide (intermediate 3); then reacting with 4-cyanopyridine to obtain an intermediate 4; then cyaniding with trimethylsilyl cyanide to obtain an intermediate 5; and finallyperforming dehydration and cyclization to generate topiroxostat. According to the method, initial raw materials and reagents are cheap and easily available; experimental operation is simple and controllable, extreme reaction conditions are avoided, and the method is suitable for laboratory development and even industrial production; the total yield is high, and the production cost is reduced; purity of the finished product can be ensured.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of topinostat. Background technique [0002] Gout is a crystal-associated arthropathy caused by deposition of monosodium urate (MSU), which is directly related to hyperuricemia caused by disturbance of purine metabolism and / or decreased uric acid excretion. With the improvement of people's living standards, the dietary structure has changed significantly, the intake of purine has increased significantly, the incidence of hyperuricemia and gout has increased significantly, and there is a trend of getting younger, and gout has become the second largest metabolic disease. Disease, second only to diabetes, threatens human health. The drug treatment of gout mainly includes two aspects, one is to control the blood uric acid level, and the other is to control the acute attack of gout. [0003] Topiroxostat, chemical name: 5-(2-cyano-4-pyridyl)-3-(4-pyridy...

Claims

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Application Information

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IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 孙哲
Owner 孙哲
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