- Synthesis method of 4-fluoroisoquinoline-5-sulfonyl chloride or pharmaceutically acceptable salt thereof
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The invention relates to a synthesis method of 4-fluoroisoquinoline-5-sulfonyl chloride, which comprises the following steps of: (1) taking isoquinoline-5-sulfonic acid as an initial raw material, oxidizing nitrogen atoms in an isoquinoline ring of the isoquinoline-5-sulfonic acid under the condition that a sulfonic acid group is protected, and then isomerizing to obtain an intermediate with substituted 1-position hydroxyl; and (2) carrying out fluorination on the intermediate with substituted 1-position hydroxyl to obtain an intermediate with substituted 1-position hydroxyl and substituted 4-position fluorine, then carrying out halogen substitution on the hydroxyl of the intermediate with substituted 1-position hydroxyl and substituted 4-position fluorine, removing halogen atoms, deprotecting sulfonic acid groups, and then carrying out acylating chlorination to obtain 4-fluoroisoquinoline-5-sulfonyl chloride. The invention also relates to a synthesis method of a pharmaceutically acceptable salt of the 4-fluoroisoquinoline-5-sulfonyl chloride. The synthesis route disclosed by the invention has the advantages of safety, controllability, high operability, low cost and the like in industrial production.
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- Method for preparing isoquinoline hydrochloride intermediate and Rho kinase inhibitor by using BTC/Ph3PO chlorination system
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The invention discloses a method for preparing an isoquinoline hydrochloride intermediate and an Rho kinase inhibitor by using a BTC/Ph3PO chlorination system, which comprises the following steps: putting an isoquinoline 5-sulfonic acid compound, BTC and a catalytic amount of Ph3PO into a reaction bottle, adding an organic solvent A, uniformly mixing all the components, and heating the mixture toreact; after the reaction is finished, carrying out suction filtration and drying to obtain a white solid isoquinoline hydrochloride intermediate, which is the isoquinoline 5-sulfonylchloride hydrochloride compound; concentrating a mother liquor part of the filtrate for separating out Ph3PO at a low temperature, and washing Ph3PO with a low-polarity solvent for recycling use. The method has the advantages of few side reactions, high product quality, less three-waste pollution, high atom economy and the like, the invention also provides a method for further preparing the Rho kinase inhibitor byutilizing the prepared isoquinoline hydrochloride intermediate; the impurities in the Rho kinase inhibitor prepared by the method are obviously lower than those in medicines obtained by a traditionalmethod.
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Paragraph 0100-0111
(2020/11/23)
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- A Practical synthesis of novel Rho-kinase inhibitor, (S)-4-fluoro-5-(2- methyl-1,4-diazepan-1-ylsulfonyl)-isoquinoline
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A practical synthesis of novel Rho-kinase inhibitor, (S)-4-fluoro-5- (2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline hydrochloride dihydrate (1) was achieved in a pilot-scale production. We have demonstrated the regioselective chlorosulfonylation of 4-fluoroisoquinoline in an one-pot reaction to afford 4-fluoroisoquinoline-5-sulfonyl chloride and the asymmetric construction of the (S)-2-methyl-1,4-diazepane moiety as key steps. The Japan Institute of Heterocyclic Chemistry.
- Gomi, Noriaki,Ohgiya, Tadaaki,Shibuya, Kimiyuki,Katsuyama, Jyunji,Masumoto, Masayuki,Sakai, Hitoshi
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experimental part
p. 1771 - 1781
(2011/09/21)
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- PROCESS FOR PRODUCTION OF 4-FLUOROISOQUINOLINE-5-SULFONYL HALIDE OR SALT THEREOF
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To provide an effective and simple process for producing 4-fluoroisoquinoline-5-sulfonyl halide or a salt thereof, and a simple method for separating for purification of the product from a by-produced position isomer thereof. The process for producing 4-fluoroisoquinoline-5-sulfonyl halide or a salt thereof, characterized in that the process includes reacting 4-fluoroisoquinoline or a salt thereof with sulfuric anhydride in the presence or absence of sulfuric acid, to thereby form 4-fluoroisoquinoline-5-sulfonic acid or a salt thereof, and, subsequently, reacting the formed sulfonic acid compound with a halogenating reagent.
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- PROCESS FOR PRODUCTION OF 4-FLUOROISOQUINOLINE-5-SULFONYL HALIDE OR SALT THEREOF
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A process for production of a 4-fluoroisoquinoline-5-sulfonyl halide or a salt thereof comprising the steps of reacting 4-fluoroisoquinoline or a salt thereof with sulfuric anhydride in the presence or absence of sulfuric acid to give 4-fluoroisoquinoline-5-sulfonic acid or a salt thereof, and then reacting the resulting 4-fluoroisoquinoline-5-sulfonic acid or salt thereof with a halogenation reagent to give a 4-fluoroisoquinoline-5-sulfonyl halide or a salt thereof. This process can produce a 4-fluoroisoquinoline-5-sulfonyl halide or a salt thereof effectively and easily and can also separate and purify the 4-fluoroisoquinoline-5-sulfonyl halide or salt thereof from a position isomer by-product easily.
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Page/Page column 8-9
(2008/06/13)
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