906820-08-4

Usage

Synthesis

Different sources of media describe the Synthesis of 906820-08-4 differently. You can refer to the following data:
1. To a 200-mL-capacity reactor equipped with a stirrer, a thermometer, a condenser, and a dropper, sulfuric anhydride (94.3 g, 1.18 mol) which had been liquefied through heating at 20°C to 35°C was added, and the internal temperature was adjusted to 26°C to 34°C. While the internal temperature was maintained, 4-fluoroisoquinoline sulfuric acid salt (33.33 g, 0.136 mol) produced in Example 2 was gradually added to the reactor. Thereafter, the internal temperature of the reactor was adjusted to 30°C, and the content was stirred for 13 hours. Thionyl chloride (89.0 g, 0.75 mol) was added dropwise to the reaction mixture, followed by heating to 70°C and stirring for four hours. After completion of reaction, the reactor was cooled. Water (333 mL), ice (600 g), and methylene chloride (500 mL) were added to another reactor (capacity: 3 L), and the reactor was cooled to 0°C or lower. While the internal temperature was carefully controlled so as not to exceed 5°C, the reaction mixture was gradually added dropwise to the reactor. Subsequently, sodium hydrogencarbonate (330 g) was gradually added to the mixture while the internal temperature was maintained at 5°C to 10°C, and the formed inorganic salt was removed through filtration. The filtrate was separated, and the aqueous layer was extracted with methylene chloride (333 mL). Collected organic layers were combined, and the combined organic layer was washed with saturated brine (166 mL), followed by drying through addition of sodium sulfate anhydrate (21 g) to the washed layer. After removal of the drying agent through filtration, methylene chloride was added to the organic layer so as to adjust the total volume to 1.2 L. Then, 4N HC1/EtOAc (41 mL) was added dropwise to the organic layer at 18 to 21°C, followed by stirring at 30°C for one hour. The precipitated crystals were collected through filtration and washed with methylene chloride (110 mL), to thereby yield 17.42 g of 4-fluoroisoquinoline-5-sulfonyl chloride hydrochloride (45.4%) as white crystals.
2. 4-Fluoro-5-isoquinolinesulfonyl chloride hydrochloride (1:1) can be used as organic synthesis intermediate and pharmaceutical intermediate, mainly used in laboratory research and development process and chemical production process.

Upstream product

• 906820-09-5 4-fluoroisoquinoline sulfate 
• 7783-05-3 disulfuric acid 
• 394-67-2 4--fluoroisoquinoline 
• 906820-10-8 4-fluoroisoquinoline-5-sulfonic acid 
• 27655-40-9 isoquinoline-5-sulfonic acid 

Downstream Products

• 223644-02-8 4-fluoro-5-[[(2S)-hexahydro-2-methyl-1H-1,4-diazepin-1-yl]sulfonyl]isoquinoline hydrochloride 
• 223645-67-8 ripasudil 

Relevant academic research and scientific papers

Synthesis method of 4-fluoroisoquinoline-5-sulfonyl chloride or pharmaceutically acceptable salt thereof

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.

Method for preparing isoquinoline hydrochloride intermediate and Rho kinase inhibitor by using BTC/Ph3PO chlorination system

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.

A Practical synthesis of novel Rho-kinase inhibitor, (S)-4-fluoro-5-(2- methyl-1,4-diazepan-1-ylsulfonyl)-isoquinoline

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.

PROCESS FOR PRODUCTION OF 4-FLUOROISOQUINOLINE-5-SULFONYL HALIDE OR SALT THEREOF

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.

PROCESS FOR PRODUCTION OF 4-FLUOROISOQUINOLINE-5-SULFONYL HALIDE OR SALT THEREOF

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.