Preparation method of lesinurad intermediate namely 1-naphthyltriazole thioketone

A technology of thiosemicarbazide and C1-C3, which is applied in the field of medicine and can solve problems such as difficult operation, long reaction time, and low yield

Inactive Publication Date: 2016-02-10
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In summary, the disadvantages of the process of preparing 3 from 1 disclosed in the literature are very obvious: the reaction time is very long, the operation of distilling and removing high-boiling DMF used in the process is relatively difficult, column chromatography is used for purification, and the yield is low

Method used

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  • Preparation method of lesinurad intermediate namely 1-naphthyltriazole thioketone
  • Preparation method of lesinurad intermediate namely 1-naphthyltriazole thioketone
  • Preparation method of lesinurad intermediate namely 1-naphthyltriazole thioketone

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024]

[0025] A. Preparation of Compound 2-C2

[0026] Add 9.11g (0.1mol) thiosemicarbazide (2-A), 17.10g (0.1mol) benzyl bromide and 50mL absolute ethanol in a 500mL round bottom flask, then heat and reflux for 30min, at this time TLC analysis found that the reaction Finish.

[0027] The reaction compound was cooled to room temperature, and 200 mL of water was slowly added under stirring, followed by 22.53 g (0.1 mol) of compound 1 and a sodium carbonate solution prepared from 5.30 g (0.05 mol) of sodium carbonate and 25 mL of water. After the addition, the reaction mixture was continued to stir at room temperature for 10 hours to obtain a white slurry, the solid was collected by suction filtration, and then vacuum-dried at room temperature to obtain compound 2-C1, 32.53g, yield 80% (1→2) , ESI-MS, m / z=407 ([M+H] + ).

[0028] B. Preparation of compound 3

[0029] 28.46 g (0.07 mol) of the above-prepared compound 2-C1 and 300 mL of absolute ethanol were refluxed for ...

Embodiment 2

[0032] Add 9.11g (0.1mol) thiosemicarbazide (2-A), 17.10g (0.1mol) benzyl bromide and 50mL absolute ethanol in a 500mL round bottom flask, then heat and reflux for 30min, at this time TLC analysis found that the reaction Finish.

[0033] The reaction compound was cooled to room temperature, and 100 mL of water was slowly added with stirring, followed by the addition of 22.53 g (0.1 mol) of compound 1 and a sodium carbonate solution prepared from 6.91 g (0.05 mol) of potassium carbonate and 25 mL of water. After the addition was complete, the reaction mixture was stirred at 50°C for an additional 3 hours, at which time TLC indicated that the reaction was complete. The resulting reaction mixture was poured into 200 mL of ice water, stirred, extracted with 200 mL×4 ethyl acetate, combined organic phases, washed with 100 mL of brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, and the filtrate was evaporated to dryness on a rotary eva...

Embodiment 3-11

[0037] Adopt the technology of embodiment 1-2, change R and X, also can realize the object of the present invention, as shown in the table below.

[0038]

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Abstract

The invention discloses a preparation method of an intermediate, which can be used to prepare the drug lesinurad for treating gout. The intermediate is 3-amino-4-(4-cyclopropylnaphthalene-1-yl)-1H-1,2,4-triazole-5(4H)-thioketone(3). The preparation method has the advantages of short reaction time, high yield, and no need of column chromatography purification.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a 3-amino-4-(4-cyclopropylnaphthalene-1-yl)-1H-1,2,4-tri-3-amino-4-(4-cyclopropylnaphthalene-1-yl) intermediate which can be used to prepare gout treatment drug lesinurad Process for the preparation of azole-5(4H)-thiones. Background technique [0002] Gout is a chronic metabolic disease characterized by hyperuricemia and pain caused by deposition of monosodium uric acid (MSU) in joints and other parts. The main reason is purine metabolism disorder and / or uric acid excretion disorder. There are tens of millions of gout patients worldwide. Lesinurad (RDEA594) is an oral drug developed by Ardea that can inhibit the uric acid transporter (uratetransporter1, URAT1) in the kidney and excrete uric acid in the blood. It was first developed from Valeant's antiviral drug RDEA806 (as shown in the following formula) . Now the ownership of lesinurad belongs to AstraZeneca. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/14
Inventor 赵桂龙田禾蔡文娜刘钰强谢亚非徐为人汤立达邹美香
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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