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Preparation method of topiroxostat

A technology of topicastat and an intermediate, which is applied in the field of pharmaceutical synthesis, can solve the problems of high price of 4-cyanopyridine nitrogen oxide, large environmental pollution, small supply and the like, and achieves low cost of raw materials, high purity, The effect of reducing usage

Inactive Publication Date: 2021-12-17
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0020] Although the route is short and the steps are simple, one of the starting materials, 4-cyanopyridine nitrogen oxide, is expensive, and the market supply is less; the second step cyanide agent zinc cyanide needs to be greatly excessive (3.0eq ), and the yield is not high, about 66%, which is relatively polluting to the environment

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

[0062] A preparation method of Topicastat, comprising the steps of:

[0063] (1) Preparation of Intermediate 1:

[0064]

[0065] The starting material isonicotinic acid (20.0g, 0.16mol, 1.0eq) was dissolved in acetic acid (100mL), and hydrogen peroxide (54.4g, content 30%, 0.48mol, 3.0eq) was added at room temperature (about 25°C), The temperature was raised to 90°C for 8h. 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 obtained solid was air-dried at 45° C. for 10 h. 20.91 g of the product was obtained, yield: 93.9%.

[0066] (2) Preparation of Intermediate 2:

[0067]

[0068] Intermediate 1 (10.0g, 71.9mmol, 1.0eq) was dissolved in methanol (80mL), concentrated sulfuric acid (5.0g) was added dropwise, the reflux reaction temperature was controlled at 64°C, and the reflux reaction was c...

Embodiment 2

[0084] With the preparation method of topicastat described in embodiment 1, the difference is:

[0085] Step (1) Preparation of Intermediate 1:

[0086] 28.0 g of the starting material isonicotinic acid was dissolved in 100 mL of acetic acid, 60.2 g of hydrogen peroxide was added at room temperature, and the temperature was raised to 80° C. for 9 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 obtained solid was air-dried at 45° C. for 10 h.

Embodiment 3

[0088] With the preparation method of topicastat described in embodiment 1, the difference is:

[0089] Step (2) Preparation of Intermediate 2:

[0090] Dissolve 18.0g of Intermediate 1 in 80mL of methanol, add 6.0g of concentrated sulfuric acid dropwise, control the reflux reaction temperature to 68°C, and reflux for 8 hours. TLC shows that there is a small amount of raw material remaining. Stop heating, cool down in an ice-water bath, and add sodium carbonate solid in batches , control the temperature not to exceed 20°C, adjust the pH to 7, filter, rinse the filter cake twice with a small amount of methanol, evaporate the methanol to dryness under reduced pressure at 45°C, dissolve the obtained solid in dichloromethane (100mL), and wash with 5 % sodium carbonate aqueous solution 15mL washed once, the dichloromethane phase was separated, dried with a little sodium sulfate, and evaporated to dryness under reduced pressure at 45°C to obtain the product.

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Abstract

The invention relates to a preparation method of topiroxostat, which comprises the steps of taking isonicotinic acid as an initial raw material, taking acetic acid as a solvent, and reacting with hydrogen peroxide to generate an intermediate 1; reacting the intermediate 1 with methanol under the catalysis of concentrated sulfuric acid to generate an intermediate 2; carrying out reflux reaction on the intermediate 2 and hydrazine hydrate in methanol to generate an intermediate 3; carrying out reflux reaction on the intermediate 3 and 4-cyanopyridine to generate an intermediate 4; and reacting the intermediate 4 with trimethylsilyl cyanide to introduce a cyano group to generate an intermediate 5, and carrying out ring closing on the intermediate 5 under the action of inorganic acid by taking 2-butanol as a solvent to generate the target product topiroxostat. The raw materials and reagents are cheap and easy to obtain, the cost of the raw materials is low, the reaction conditions of each step are mild, the operation is simple, and the controllability is strong; and the large-scale industrial production and application can be realized. The yield is high, the purity is high, the total yield is 51.4%, the refining yield is 91.8%, the purity of the refined product reaches 99.82%, and the single impurity content is less than 0.1%.

Description

technical field [0001] The invention relates to a preparation method of topicastat, which belongs to the field of drug synthesis. 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-pyridyl)-1,2,4-tri...

Claims

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Application Information

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IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 孙哲马晨
Owner SHANDONG UNIV
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