Preparation method of Roxadustat intermediate

Abstract

The invention provides a preparation method of a Roxadustat intermediate, and particularly relates to a preparation method of a Roxadustat intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline carboxylate. The preparation method comprises the following steps: carrying out a halogenation reaction on 4-hydroxy-1-hydrogen-7-phenoxy-3-isoquinoline carboxylate and a halogenating agent in the presence of a solvent to prepare 4-hydroxy-1-chloro / bromo / iodine-7-phenoxy-3-isoquinoline carboxylate, and further carrying out a methylation reaction in the presence of a catalyst, an alkali and a solvent to prepare 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline carboxylate. The preparation method provided by the invention has the advantages of easily available raw materials, mature and controllable process route and high reaction yield so as to be beneficial to industrial production of bulk drugs.

Description

technical field [0001] The present invention relates to a preparation method of Roxadustat (Roxadustat) intermediate used for treating chronic anemia. Background technique [0002] The chemical name of Roxadustat is N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline)carbonyl]glycine, and its structural formula is: [0003] [0004] Roxadustat (Roxadustat) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor originally developed by FibroGen in the United States and currently co-developed with AstraZeneca. It can be used for the treatment of chronic anemia, code-named FG- 4592. In the current phase III multi-center clinical trial of the original research, on October 31, 2017, the Japanese phase III release positive results for anemia in peritoneal dialysis patients with chronic kidney disease who had received or not received ESAs (erythropoiesis-stimulating agents) treatment. [0005] The existing related technologies for preparing Roxadustat or its key int...

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Problems solved by technology

[0020] However, in the above-mentioned method 1), when preparing the intermediate 4-hydroxyl-1-methyl-7-phenoxy-3-isoquinoline carboxylate, bromination is carried out using phosphorus oxybromide, which has a high risk of amplifying production safety , the further methylation step is prepared by the method of n-butyllithium and methyl iodide, the safety risk of large-scale production is high, and the yield is low

[0021] In the above method 2), when preparing the intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline carboxylate, phosphorus oxychloride is used for chlorination, and the safety risk of enlarged production is high; Methylation method uses palladium catalyst, methylborane preparation (trimethylboron, tetrakistriphenylphosphine palladium, potassium carbonate, 1,4-dioxane as solvent), low yield, and trimethylboron Alkanes are dangerous goods, easy to spontaneous combustion, not conducive to industrial amplification

[0022] In the above-mentioned method 3), when preparing the intermediate 4-hydroxyl-1-methyl-7-phenoxy-3-isoquinoline carboxylate, the reduction of the amine is used to realize the introduction of the methyl group. Protection and deprotection, the reaction steps are lengthy, and deprotection needs to be obtained by hydrogenation, the preparation process is relatively cumbersome, special hydrogenation equipment is required, and the preparation cost is high

[0023] In the above method 4), when preparing the intermediate 4-hydroxyl-1-methyl-7-phenoxy-3-isoquinoline carboxylate, it is prepared by the amino acid ring closure method, in which the phenolic hydroxyl group is introduced into the phenyl In the process, it is easy to generate amino-substituted by-products, which brings difficulties to the purification of the final product, and the introduction of the 4-hydroxyl group on the isoquinoline ring adopts the hydrogen peroxide oxidation method, which has a greater safety hazard in the industrial production process

[0024] In the above method 5), when preparing 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline carboxylate, the method of introducing the front end of the methyl group is used to prepare the key intermediate 3-methyl- 5-bromoisopropylbenzofuran-1-(3H)-one, the process of preparing this key intermediate needs to use oxidant iodobenzenediethyl ester and reducing agent sodium borohydride respectively; the post-treatment process of these two steps of operation all adopts direct concentration Very dry operation, high safety risk, not conducive to industrial scale-up

[0025] In the above-mentioned method 6), when preparing 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline carboxylate, it is prepared by amine and ketomalonate diester ring closure method, the method The disadvantage is that the key intermediate ketomalonate diester is expensive, and the self-made intermediate is mostly prepared by oxidation with an oxidant, and the industrial scale-up safety risk of the self-made intermediate is high; if the purchase route is expensive

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