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Preparation method of Lesinurad

A compound, selected technology, applied in chemical instruments and methods, compounds containing periodic table Group 3/13 elements, bulk chemical production, etc. problem, to achieve the effect of low cost, high reliability and short process route

Active Publication Date: 2018-04-24
成都美域高制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Compared with route 1, although route 2 has a shorter route and a relatively higher yield, it also uses sodium nitrite, a strong carcinogen, and carbon disulfide reagent, which is toxic and has a foul smell, causing great harm to the health of operators. In addition, highly toxic hydrazine hydrate is used in route two, which is difficult to handle and causes great environmental pollution. Even if the sewage discharge is qualified, the sewage discharge fee is also very high, resulting in a sharp increase in production costs, which is not conducive to commercial production

Method used

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  • Preparation method of Lesinurad
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  • Preparation method of Lesinurad

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] The synthetic method of embodiment 1 Resinard

[0052] (1) Synthesis of Les-03

[0053]

[0054] Put 572mg of 1,4-dibromo-naphthalene in a 100mL flask, add 20mL of dioxane and 20mL of 2mol / L potassium carbonate solution, stir well, then continue to add 176mg of cyclopropylboronic acid and 100mg of tetrakis(triphenyl Phosphine) palladium, then pass through nitrogen exchange for 10 minutes, under the protection of nitrogen, heat and reflux at 100°C for 4 hours, HPLC detection reaction, after the reaction is completed, add 20mL ethyl acetate to the reaction solution for extraction, continuous extraction for 2 Then add saturated brine to wash twice, 20 mL each time, combine the organic phases, concentrate under reduced pressure, and filter to obtain 430 mg of 1-bromo-4-cyclopropyl-naphthalene, with a yield of 87% and a purity of 96.5%.

[0055] (2) Synthesis of Les-05

[0056]

[0057] Put 250mg of 1-bromo-4-cyclopropyl-naphthalene in a 100mL flask, add 5mL of dioxa...

Embodiment 2

[0067] The synthetic method of embodiment 2 Resinard

[0068] (1) Synthesis of Les-03

[0069]

[0070] Put 28.6g of 1,4-dibromo-naphthalene in a 10L flask, add 1L of dioxane and 1L of 2mol / L sodium carbonate solution, stir well, then continue to add 17.6g of cyclopropylboronic acid and 7.5g Tetrakis(triphenylphosphine) palladium, then pass through nitrogen exchange for 10 minutes, under the protection of nitrogen, heat and reflux at 100°C for 5 hours, HPLC detects the reaction, after the reaction is completed, add 2L ethyl acetate to the reactant for extraction , continuously extracted 2 times, then added saturated brine to wash 2 times, 2L each time, combined the organic phases, concentrated under reduced pressure, and filtered to obtain 18.8g of 1-bromo-4-cyclopropyl-naphthalene, with a yield of 76.4%; purity was 96.1%.

[0071] (2) Synthesis of Les-05

[0072]

[0073] Place 12.5g of 1-bromo-4-cyclopropyl-naphthalene in a 10L flask, add 0.5L of dioxane solvent to ...

Embodiment 3

[0083] The synthetic method of embodiment 3 Resinard

[0084] (1) Synthesis of Les-03

[0085]

[0086] Place 286g of 1,4-dibromo-naphthalene in a 100L flask, add 10L of tetrahydrofuran and 10L of triethylamine, stir well, then continue to add 176g of cyclopropylboronic acid and 75g of tetrakis(triphenylphosphine)palladium, Then pass through nitrogen exchange for 15 minutes, under the protection of nitrogen, heat and reflux at 100°C for 5 hours, HPLC detects the reaction, after the reaction is completed, add 20L ethyl acetate to the reactant for extraction, continuous extraction 2 times, and then add saturated Wash with brine twice, 20 L each time, combine the organic phases, concentrate under reduced pressure, and filter to obtain 185 g of 1-bromo-4-cyclopropyl-naphthalene, with a yield of 75.2% and a purity of 95.6%.

[0087] (2) Synthesis of Les-05

[0088]

[0089] Place 125g of 1-bromo-4-cyclopropyl-naphthalene in a 100L flask, add 0.5L tetrahydrofuran solvent to ...

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Abstract

The invention discloses a preparation method of Lesinurad, and belongs to the technical field of chemical drug synthesis. A compound of the formula Les-03 in the description is prepared from compoundsshown in formulas Les-01 and Les-02 as raw materials, a compound of the formula Les-04 is added, and a compound of the formula Les-05 is prepared. The compound of the Les-05 has high selectivity during coupling, so that the purity of a reaction product is high, post-treatment is facilitated, and quality of an obtained final product is controllable; the compound in Les-07 is prepared from the compound in Les-05 and the compound in Les-06 by Suzuki coupling reaction, the Suzuki coupling reaction has high reliability and good repeatability, and finally Lesinurad is obtained through protecting group removal. The preparation method has the advantages of short process route, high yield and low cost; adopted reagents are non-toxic or low-toxic conventional reagents, and are basically harmless tooperators and basically pollution-free to the environment; the whole process is simple and convenient to operate, the process stability is good, the quality of the obtained final product is controllable and stable, and the method is suitable for commercial production.

Description

technical field [0001] The invention relates to a preparation method of Lesinurad, in particular to a chemical synthesis method of Lesinurad raw material drug (Lesinurad), which belongs to the technical field of chemical medicine synthesis technology. Background technique [0002] Hyperuricemia (HUA) is one of the important components of metabolic syndrome, closely related to gout, and also a risk factor for hypertension, chronic kidney disease, dyslipidemia, diabetes and cardiovascular disease. The prevalence of HUA in western developed countries is 15-20%. In recent years, with the improvement of living standards in our country, the change of diet structure and the extension of average life expectancy, the prevalence of HUA has increased year by year. It is estimated that there are nearly 120 million patients with HUA in my country, and about 17 million patients with gout. Gout is a disease characterized by hyperuricemia and deposition of monosodium uric acid (MSU) in join...

Claims

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Application Information

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IPC IPC(8): C07F5/02C07D249/12
CPCC07D249/12C07F5/025Y02P20/55
Inventor 王春燕陈志勇随裕敏
Owner 成都美域高制药有限公司
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