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Preparation method of Lesinurad

A technology of condensation reaction and raw materials, applied in the field of preparation of new drug Lixinlord, can solve the problems of low total yield, difficult industrialization, many reaction steps, etc., and achieves the effect of environmental protection and economy, simple process, and promotion of development.

Inactive Publication Date: 2016-12-14
SUZHOU MIRACPHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] However, the preparation process of this method still needs to go through reaction processes such as nitro reduction, bromination and ester hydrolysis, and the substrates of these reactions are all based on the naphthalene ring mother ring. yield
[0012] It can be seen from this that the existing Lixinluode preparation scheme still has the problems of many reaction steps and low total yield, and is not easy to be industrialized due to the limitations of cost, equipment and environmental protection.

Method used

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  • Preparation method of Lesinurad
  • Preparation method of Lesinurad
  • Preparation method of Lesinurad

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] 1-bromo-4-cyclopropylnaphthalene (II) (12.4g, 0.05mol), 2-[(3-bromo-4H-1,2,4-triazol-5-yl)thio]acetic acid ( III) (14.3g, 0.06mol), cuprous iodide (1.42g, 7.5mmol), 8-hydroxyquinoline (2.2g, 7.5mmol), potassium carbonate 7.6g (0.055mol) and 100mL N, N-di Add methylformamide into a 250mL three-necked flask, raise the temperature to 100°C, and stir until dissolved.

[0033] Add ethylenediamine (0.45g, 7.5mmol), continue to heat up to 120 degrees, react for 5-7 hours, TLC detection, the reaction is complete. Cool down to 50-60 degrees, filter, and wash the filter cake with ethyl acetate. The organic phases were combined, washed with brine and water, concentrated, and slurried with ethyl acetate and water (9:1) to obtain 14.6 g of beige solid Lixinluode (I), with a yield of 72.3%. ESI-MS (m / z): 405 (M+H), 1 H NMR (400MHz, CDCl3) 12.92 (brs, 1H), 8.57 (d, J = 8.5Hz, 1H), 7.65 (m, 3H), 7.41 (d, J = 7.5Hz, 1H), 7.14 (d, J =7.8Hz, 1H), 3.97(s, 2H), 2.52(m, 1H), 1.14(m.2H), ...

Embodiment 2

[0035] 1-bromo-4-cyclopropylnaphthalene (II) (12.4g, 0.05mol), 2-[(3-bromo-4H-1,2,4-triazol-5-yl)thio]acetic acid ( III) (14.3g, 0.06mol), cuprous iodide (1.42g, 7.5mmol), 4-dimethylaminopyridine (0.9g, 7.5mmol), potassium tert-butoxide 6.2g (0.055mol) and 100mL dimethyl Add sulfoxide into a 250mL three-necked flask, raise the temperature to 100°C, and stir until dissolved.

[0036] Add diisopropylethylamine (1.0 g, 7.5 mmol), continue to heat up to 130 degrees, and react for 6 to 8 hours. TLC detects that the reaction is complete. Cool down to 50-60 degrees, filter, and wash the filter cake with ethyl acetate. The organic phases were combined, washed with brine and water, concentrated, and slurried with ethyl acetate and water (9:1) to obtain 13.5 g of beige solid Lixinluode (I), with a yield of 66.8%.

Embodiment 3

[0038] 2-[(3-amino-4H-1,2,4-triazol-5-yl)thio]acetic acid (IV) (8.7g, 0.05mol) and 48% concentration of hydrobromic acid (15mL, 0.125 mol) into a 100mL single-port reaction flask, lower the temperature to 0°C, add dropwise a 10mL aqueous solution of sodium nitrite (3.5g, 0.05mol) under stirring, keep the temperature between 5°C and 10°C, and drop it in about 30 minutes. spare.

[0039] Add cuprous bromide (3.9g, 27.5mmol) and 48% concentration of hydrobromic acid (4mL, 0.03mol) in a 100mL three-necked flask, stir and dissolve, place in an ice bath, add the above-mentioned standby solution dropwise, and keep The temperature is 5-10 degrees. After dropping, raise the temperature to room temperature and continue to stir and react for 30 minutes, then continue to slowly raise the temperature to 50-60 degrees, stir and react until no gas overflows, and stop the reaction. Stand still, filter, and recrystallize the filter cake with ethanol and water (volume ratio 1:1) to obtain off...

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Abstract

The invention discloses a preparation method of a novel drug Lesinurad for gout treatment. The preparation method comprises the preparation step that Lesinurad is prepared by taking 1-bromo-4-cyclopropyl naphthalene and 2-[(3-bromo-4H-1,2,4-triazole-5-yl)sulfo]acetic acid as raw materials through a condensation reaction in one step. According to the preparation method of Lesinurad, the raw materials are easy to obtain, the process is simple, the economical property and environmental friendliness are achieved, and the method is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and particularly relates to a preparation method of a new drug Lesinurad for treating gout. Background technique [0002] Lesinurad, developed by Ardea Biosciences, a subsidiary of AstraZeneca, is a selective uric acid reabsorption inhibitor (SURI) that selectively inhibits the urate transporter URAT1, which is responsible for the renal resorption of most uric acid in the urine. absorb. By inhibiting URAT1, Lesinurad is able to increase uric acid excretion, thereby reducing serum uric acid (sUA) levels. The drug was approved by the U.S. FDA in December 2015, with the product name Zurampic; in February 2016, the European Union EMEA also approved the drug for the treatment of gout, providing patients with a new choice. Since Lesinurad does not yet have a standard Chinese translation, the applicant here transliterates it as ...

Claims

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Application Information

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IPC IPC(8): C07D249/12
CPCC07D249/12
Inventor 许学农
Owner SUZHOU MIRACPHARMA TECH
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