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Preparation method of lesinurad oxidation impurity

A technology for oxidizing impurities and compounds, which is applied in the field of preparation of oxidized impurities in Recinard, and can solve the problems of oxidized impurities and other problems

Pending Publication Date: 2021-05-11
HAINAN XINOPEN SOURCE MEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] However, the above preparation method will produce oxidized impurities in the process of synthesizing intermediates

Method used

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  • Preparation method of lesinurad oxidation impurity
  • Preparation method of lesinurad oxidation impurity
  • Preparation method of lesinurad oxidation impurity

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[0034] The invention provides a method for preparing the oxidized impurities of Lecinard, comprising: S1) oxidizing the compound represented by the formula (II) under alkaline conditions, then adjusting the pH value of the reaction solution to acidity, and then reacting with the quaternary ammonium salt reaction to obtain a compound shown in formula (III); S2) dissolving the compound shown in formula (III) in a mixed solvent of water and the first organic solvent, adjusting the pH value to acidity, and then separating the organic phase Solvent is removed to obtain the oxidized impurity of Leycinard shown in formula (I);

[0035]

[0036] Wherein, R is a C1-C10 alkyl group, preferably a C2-C8 alkyl group, more preferably a C3-C6 alkyl group, and still more preferably a C4-C5 alkyl group.

[0037] Taking R as a butyl group as an example, the synthetic route is:

[0038]

[0039] The compound represented by formula (II) is oxidized under basic conditions; the reaction is p...

Embodiment 1

[0053] Step 1: Add 100ml of purified water and sodium hydroxide (1.15g, 0.0289mol) to a 1L three-necked flask, stir to dissolve, and then add 5-bromo-4-(4-cyclopropylnaphthalene- 1-yl)-4H-1,2,4-triazole-3-thiol (10.00g, 0.0289mol), heated to reflux, then added potassium permanganate (9.13g, 0.0578mol), and refluxed to complete , cool to room temperature, filter, collect the filtrate, adjust the filtrate to pH 5-6 with acetic acid, add tetrabutylammonium acetate (13g, 0.0434mol) to the filtrate, stir until the reaction is complete, then use 200ml, 100ml dichloro Extract the reaction solution with methane, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate to dryness, add 50ml of methyl isobutyl ketone and stir to dissolve, slowly cool down to 7°C for crystallization for 3 hours, filter, and vacuum-dry at 50°C to obtain a light yellow solid .

[0054] Add the light yellow solid obtained in step 1 to a 500ml three-neck flask, heat 200ml of ethy...

Embodiment 2

[0057] Step 1: Add 500ml of purified water and sodium hydroxide (1.15g, 0.0289mol) to a 1L three-necked flask, stir to dissolve, and then add 5-bromo-4-(4-cyclopropylnaphthalene- 1-yl)-4H-1,2,4-triazole-3-thiol (10.00g, 0.0289mol), heated to reflux, then added 30% hydrogen peroxide (11.6ml, 0.1156mol), and refluxed to complete, cool down to room temperature, filter, collect the filtrate, adjust the filtrate to pH 5-6 with acetic acid, add tetrabutylammonium acetate (13g, 0.0434mol) to the filtrate, stir until the reaction is complete, then use 200ml, 100ml Extract the reaction solution with methyl chloride, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate to dryness, add 50ml of methyl isobutyl ketone and stir to dissolve, slowly cool down to 6°C for crystallization for 3 hours, filter, and vacuum-dry at 50°C to obtain light yellow solid.

[0058] Add the light yellow solid obtained in step 1 to a 500ml three-necked flask, heat 230ml of is...

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Abstract

The invention provides a preparation method of a lesinurad oxidation impurity, which comprises the following steps: S1) oxidizing a compound as shown in a formula (II) under an alkaline condition, then adjusting the pH value of a reaction solution to be acidic, and conducting reacting with a quaternary ammonium salt to obtain a compound as shown in a formula (III); and S2) dissolving the compound as shown in the formula (III) in a mixed solvent of water and a first organic solvent, adjusting the pH value to be acidic, and then separating an organic phase to remove the solvent, thereby obtaining the lesinurad oxidation impurity as shown in a formula (I). Compared with the prior art, the synthetic method disclosed by the invention is simple, the obtained sample is high in purity, the method can be used for the links of process research and development, production, quality standard establishment and quality control of the lesinurad, and a technical support is provided for the medication safety of the lesinurad.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of Lecinard oxidized impurities. Background technique [0002] Gout is a crystal-associated arthropathy caused by the deposition of mountain monosodium urate (MSU), which is directly related to the hyperuricemia caused by the disturbance of purine metabolism and / or the decrease of uric acid excretion. There are more than 20 million gout patients worldwide. Lesinurad (RDEA594, Lesinurad) is an oral uricosuric agent that inhibits the renal proximal tubule uric acid transporter URAT1. Allopurinol (ALLO) combined with lesinurad was more effective in reducing serum uric acid (SUA) than ALLO alone in an exploratory study in patients with previous gout. Moreover, through the study of more than 500 healthy people and gout patients, it was found that Lesinurad reduced blood uric acid in a dose-dependent manner, and Febuxostat was well tolerated...

Claims

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Application Information

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IPC IPC(8): C07D249/12C07D231/18
CPCC07D249/12C07D231/18
Inventor 王海霞夏兵吴进
Owner HAINAN XINOPEN SOURCE MEDICAL TECH CO LTD
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