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Synthetic method of Lesinurad

A synthesis method and compound technology, applied in the direction of organic chemistry, can solve the problems of unfavorable industrialization, etc., and achieve the effect of less side reactions, simple and easy preparation method, and high purity

Active Publication Date: 2017-06-20
ZHEJIANG MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] This route uses highly toxic liquid bromine during bromination, which is not conducive to the realization of industrialization

Method used

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  • Synthetic method of Lesinurad

Examples

Experimental program
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Effect test

Embodiment 1

[0042] The synthetic method of Lesinurad in the present embodiment comprises the following steps:

[0043] (1) At room temperature, mix 100g of the compound of formula 7, 500mL of DMF, and 48g of methyl carbazate into the reaction flask, heat the reaction mixture to 50-60°C, and keep stirring for 5-8 hours; the reaction is over Afterwards, the reaction solution was cooled to room temperature, and 4000 mL of water was added to precipitate the product, filtered and dried to obtain 125 g of the dry product of the compound of formula 6, with a yield of 89%;

[0044] (2) Add 100g of the compound of formula 6 to 1500mL of 1M sodium hydroxide solution at room temperature, heat to 80-90°C for 1 hour to dissolve, cool to room temperature after TLC detection, add dropwise 3500mL of 5% hydrochloric acid solution to precipitate The solid was filtered to obtain a wet product, and dried in a hot air oven at 55°C to constant weight to obtain 85 g of the dry product of the compound of formula...

Embodiment 2

[0049] (1) At room temperature, mix 50g of the compound of formula 7, 300mL of DMF, and 24g of methyl carbazate and add them to the reaction flask, heat the reaction mixture to 50-60°C, and keep stirring for 7 hours; The reaction solution was cooled to room temperature, and 2500 mL of water was added to precipitate the product, filtered and dried to obtain 60 g of the compound of formula 6 as a dry product, with a yield of 88%;

[0050] (2) Add 50g of the compound of formula 6 to 700mL of 1M sodium hydroxide solution at room temperature, heat to 80-90°C for 1 hour to dissolve, cool to room temperature after TLC detection, add dropwise 1750mL of 5% hydrochloric acid solution to precipitate The solid was filtered to obtain a wet product, and dried in a hot air oven at 55°C to constant weight to obtain 42 g of the dry product of the compound of formula 5, with a yield of 95%;

[0051] (3) At room temperature, mix 0.1 mol of the compound of formula 5 with potassium carbonate and D...

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Abstract

The invention relates to a synthetic method of Lesinurad. The method comprises the following steps: carrying out a nucleophilic addition reaction on an initial raw material 1-cyclopropylnaphthalene-4-yl-isorhodanate (compound 7) and methyl hydrazinocarboxylate to generate a compound 6, cyclizing the compound 6 under the action of sodium hydroxide to generate a compound 5, carrying out a condensation reaction on the compound 5 and a compound 4 to remove one molecule of halogen hydride in order to generate a compound 3, brominating the compound 3 to generate a compound 2, and hydrolyzing the compound 2 under the action of an alkali to obtain the target product Lesinurad. The preparation method is simple and easy; the compound 2 is prepared through carrying out the nucleophilic addition reaction on the hydroxyl group of the compound 3 by an introduced bromine atom, so generation of an alpha-bromocarboxylic acid impurity in the target product is avoided; the purity of the reaction product is high and reaches 99.5% or above; side reactions are few, so the yield of the target product is high and reaches 96%; and most raw materials used in the whole preparation process are nontoxic, so industrial production of the target product is conveniently realized.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a new synthesis method of Lesinurad. Background technique [0002] Gout is a crystal-associated arthropathy caused by the precipitation of monosodium urate, which is directly related to hyperuricemia caused by disturbance of purine metabolism and decreased uric acid excretion. Lesinured is an oral uricosuric drug that inhibits the renal proximal tubule uric acid transporter URAT1 for the treatment of gout patients with hyperuricemia. The chemical name of Lesinurad is 2-[[5-bromo-4-(4-cyclopropyl-1-naphthalene)-4H-1,2,4-triazol-3-yl]thio]acetic acid, and the CAS number is 878672-00-5, the chemical structural formula of the drug is as follows: [0003] [0004] Initially, this compound was developed from compound 5 (RDEA806) synthesized by Valeant in 2006, and its synthetic route is as follows: [0005] [0006] Soon after, Ardea Bio discovered Lesinurad which...

Claims

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Application Information

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IPC IPC(8): C07D249/12
CPCC07D249/12Y02P20/55
Inventor 余奎黄想亮黄勤陈为人姚成志
Owner ZHEJIANG MENOVO PHARMA
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