The synthetic method of 7-fluoroisoquinoline-1-carboxylic acid

Abstract

The invention discloses a method for synthesizing 7-fluoroisoquinoline-1-carboxylic acid. The method uses 5-fluoro-2-methylbenzoic acid as a raw material to obtain 5-fluoroisoquinoline-1-carboxylic acid through condensation with N,N-carbonyldiimidazole ‑Fluoro‑2‑methylbenzamide reacted with N,N‑dimethylformamide dimethyl acetal （E） ‑N‑((dimethylamino)methylene)‑5‑fluoro‑2‑methylbenzamide, followed by cyclization in potassium tert-butoxide to give 7‑fluoroisoquinoline‑1‑alcohol, which is then reacted with tribromo Oxon reaction generates 1-bromo 7-fluoroisoquinoline, and then under carbon monoxide conditions, 7-fluoroisoquinoline-1-carboxylate methyl ester is obtained, and finally hydrolyzed in aqueous sodium hydroxide solution to obtain 7-fluoroisoquinoline- 1‑Carboxylic acid. The method has simple synthesis route, reasonable process selection, low cost of raw materials, simple and easy-to-obtain raw materials, simple and safe operation, no use of highly toxic reagents, convenient post-treatment, high total yield, easy scale-up, and large-scale production.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and in particular relates to a synthesis method of 7-fluoroisoquinoline-1-carboxylic acid. Background technique [0002] 7-Fluoroisoquinoline-1-carboxylic acid, as a pharmaceutical intermediate of Guan Yu, has been widely used in drug design due to its unique structure. For example, combining with pyrrolidine produces a series of compounds that inhibit the NS5A protein encoded by hepatitis C virus (HCV). Compared with the original HCV drugs, this series of compounds can effectively reduce side effects and increase inhibitory activity. Therefore, such isoquinoline amide derivatives have good therapeutic potential, in which 7-fluoroisoquinoline-1-carboxylic acid plays a significant role in enhancing the inhibitory activity (WO2010138488A1). Nakayama A et al. developed a novel very late antigen-4 (Vla-4) selective inhibitor, which has significant efficacy in inflam...

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Problems solved by technology

[0003] The synthesis of 7-fluoroisoquinoline-1-carboxylic acid, the current method is to react 7-fluoro-1-bromoisoquinoline with trimethylnitrile silane to generate 7-fluoro-1-cyanoisoquinoline and then hydrolyze Finally generate 7-fluoroisoquinoline-1-carboxylic acid, yet the raw material 7-fluoro-1-bromoisoquinoline used in this method is a non-commercialized reagent, the price is relatively expensive and difficult to obtain, and the used in the reaction Trimethylnitrile silane is highly toxic and unsafe

Another synthetic method is the reaction of 7-fluoro-1-chloroisoquinoline with 2-(tributylstannyl)furan to generate 7-fluoro-1-furanisoquinoline, which is then reacted with sodium periodate to generate 7-fluoro Isoquinoline-1-carboxylic acid, the raw material 7-fluoro-1-fluoroisoquinoline used in this method is a non-commercialized reagent, the price is relatively expensive and difficult to obtain, and the carbon tetrachloride used in the reaction is poisonous, Palladium dichloride is expensive, cesium fluoride is flammable, etc.

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