A process for refining the lesinurad intermediate 1-naphthyltriazolethione that can be industrialized

Abstract

The invention discloses a synthesis process and refining process for a lesinurad intermediate 3-amino-4-(4-cyclopropylnaphthalen-1-yl)-1H-1,2,4-triazole-5(4H)-thione which can be used for preparation of gout treatment drugs. The process comprises the following steps: adding a sodium carbonate solution into a mixture prepared from a compound 1, a compound 2-B1, ethanol and water drop by drop; supplementing a proper amount of water after completion of reaction; and treating a crude product 3 of 3-M containing impurities with alkali in a solvent, hydrolyzing 3-M and subjecting the obtained crude solid of 3 to ethanol beating so as to obtain a high-purity product 3. The process has the advantages of suitability for large-scale industrial operation and capacity of producing the high-purity product.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a kind of intermediate 3-amino-4-(4-cyclopropylnaphthalen-1-yl)-1H-1,2,4 which can be used to prepare gout treatment drug lesinurad -A method for triazole-5(4H)-thione and its purification process. 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 (RDEA 594) is an oral drug developed by Ardea that can inhibit urate transporter 1 (URAT1) in the kidney and excrete uric acid in the blood. It was first developed from Valeant's antiviral drug RDEA806. Now the ownership of lesinurad belongs to Astra Zeneca. [0003] [0004] The main synthetic routes of Lesinurad (WO2014 / 008295 and US201334...

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Problems solved by technology

[0011] However, in the most potential synthetic route of 1→3 disclosed in the patent CN201410340622.9 (i.e. the embodiment 1 of CN201410340622.9, at this time R=Bn, the production rate reported in this embodiment and the cost of RX are in the The best of all possible technical options publicly available) in-depth research, especially at the pilot scale and above, found two technical problems that hinder the use of this route in industry

The first is that when compound 1 and 2-B1 react to form 2-C1 in the mixed solution of ethanol / water in the presence of alkali, the system will precipitate very viscous jelly when the reaction is carried out in the middle stage, and these substances will Attached to the stirring paddle, it is difficult to stir smoothly, which greatly affects the production safety; the second is that when preparing on the scale of pilot test and above, in-depth research found that the compound 3 obtained according to the process of Example 1 was isolated. The sample contains a certain amount of impurity 3-M (the structural formula is shown below), and the content is generally around 10%-20%

The solubility of 3-M is poor, and it is difficult to remove using the process disclosed in CN201410340622.9 (that is, beating in ethanol), which has a great influence on the sample purity of compound 3

It is also difficult to remove when trying to recrystallize using solvents such as pure ethanol or a mixture of ethyl acetate and n-hexane, and it is not easy to separate 3-M and 3 using ordinary column chromatography, because compound 3-M is less soluble , often precipitated on the silica gel column and cause column blockage during column chromatography, and column chromatography is often not used in large-scale production

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