194032-33-2

Usage

Uses

Used in Pharmaceutical Synthesis:
4-Fluoroisoquinoline-5-sulfonyl chloride is utilized as a key intermediate in the production of pharmaceuticals, specifically for the synthesis of sulfonamide-containing compounds. Its ability to react with a range of nucleophiles facilitates the creation of diverse chemical structures, which is crucial for the development of new drugs with unique therapeutic properties.
Used in Agrochemical Development:
In the agrochemical industry, 4-Fluoroisoquinoline-5-sulfonyl chloride serves as a valuable building block for the synthesis of various agrochemicals. Its incorporation into these compounds can enhance their effectiveness in agricultural applications, such as pest control and crop protection.
Used in Organic Synthesis:
4-Fluoroisoquinoline-5-sulfonyl chloride is employed as a versatile reagent in organic synthesis. Its capacity to form sulfonamide groups with nucleophiles makes it an essential component in the preparation of a wide array of organic compounds, contributing to the advancement of chemical research and the discovery of novel chemical entities.

Synthetic route

4-bromoisoquinoline (1532-97-4) → 4-aminoisoquinoline (23687-25-4) + 4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2)

4-fluoroisoquinoline-5-amine (928664-14-6) → 4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2)

Conditions	Yield
Stage #1: 4-fluoroisoquinoline-5-amine With hydrogenchloride; sodium nitrate In water at -15℃; for 1h; Inert atmosphere; Stage #2: With sulfur dioxide; acetic acid; copper(l) chloride In 1,4-dioxane; water at -5 - 0℃; for 2h;

4-­fluoroisoquinoline (394-67-2) → 4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sulfuric acid; potassium nitrate / 12 h / 25 °C / Inert atmosphere 2.1: zinc; ammonium chloride / water; tetrahydrofuran / 5 h / 25 °C / Inert atmosphere 3.1: hydrogenchloride; sodium nitrate / water / 1 h / -15 °C / Inert atmosphere 3.2: 2 h / -5 - 0 °C View Scheme

4-­fluoroisoquinoline (394-67-2) → 4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2) + C9H5ClFNO2S

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sulfuric acid / acetone / 2 h / 0 - 10 °C / Inert atmosphere; Large scale reaction 2.1: sulfur trioxide / 19 h / 30 °C / Inert atmosphere; Large scale reaction 2.2: 7 h / 30 - 70 °C / Inert atmosphere View Scheme

4-fluoroisoquinoline sulfate (906820-09-5) → 4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2) + C9H5ClFNO2S

Conditions	Yield
Stage #1: 4-fluoroisoquinoline sulfate With sulfur trioxide at 30℃; for 19h; Inert atmosphere; Large scale reaction; Stage #2: With thionyl chloride at 30 - 70℃; for 7h; Inert atmosphere;

4-bromoisoquinoline (1532-97-4) → 4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / 0.5 h / -65 °C 1.2: 11.5 h / -65 - 25 °C / Inert atmosphere 2.1: sulfuric acid; potassium nitrate / 12 h / 25 °C / Inert atmosphere 3.1: zinc; ammonium chloride / water; tetrahydrofuran / 5 h / 25 °C / Inert atmosphere 4.1: hydrogenchloride; sodium nitrate / water / 1 h / -15 °C / Inert atmosphere 4.2: 2 h / -5 - 0 °C View Scheme

4-fluoro-5-nitroisoquinoline (928664-13-5) → 4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: zinc; ammonium chloride / water; tetrahydrofuran / 5 h / 25 °C / Inert atmosphere 2.1: hydrogenchloride; sodium nitrate / water / 1 h / -15 °C / Inert atmosphere 2.2: 2 h / -5 - 0 °C View Scheme

4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2) + 2-(S)-2-amino-N-(tert-butoxycarbonyl)-N-(4-tert-butyldimethylsilyloxybutyl)propylamine (1011465-99-8) → 2-(S)-1-(4-fluoroisoquinoline-5-sulfonyl)-N-(tert-butoxycarbonyl)-N-(4-tert-butyldimethylsilyloxybutyl)propylamine (1011466-00-4)

Conditions	Yield
With triethylamine In dichloromethane at 20℃;	66%
With triethylamine; dmap In dichloromethane at 0 - 20℃; for 16h;	66.8%

4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2) + (S)-2-amino-N-(tert-butoxycarbonyl)-N-(3-tert-butyldimethylsilanyloxypropyl)propylamine (1011466-10-6) → (S)-2-(4-fluoroisoquinoline-5-sulfonamido)-N-(tert-butoxycarbonyl)-N-(3-tert-butyldimethylsilyloxypropyl)propylamine

Conditions	Yield
With dmap; triethylamine In dichloromethane at -5 - 30℃; for 16.75h;	58.2%

4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2) + hexahydro-5-methyl-1H-1,4-diazepine (22777-05-5) → 1-(4-Fluoro-5-isoquinolinesulfonyl)-5-methylhexahydro-1H-1,4-diazepine

4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2) + 2,5-dimethylpiperazine (106-55-8) → 1-(4-fluoro-5-isoquinolinesulfonyl)-2,5-dimethylpiperazine

1,4-Diazacycloheptane (505-66-8) + 4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2) → 1-(4-fluoro-5-isoquinolinesulfonyl)hexahydro-1H-1,4-diazepine

4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2) → 2-(S)-1-(4-fluoroisoquinoline-5-sulfonyl)-N-(tert-butoxycarbonyl)-N-(4-hydroxybutyl)propylamine (1011466-01-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 20 °C 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C View Scheme

4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2) → (S)-octahydro-4-(tert-butoxycarbonyl)-1-(4-fluoroisoquinoline-5-sulfonyl)-2-methyl-1,4-diazocine

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 20 °C 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C 3: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 20 °C View Scheme

4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2) → (S)-octahydro-1-(4-fluoroisoquinoline-5-sulfonyl)-2-methyl-1,4-diazocine dihydrochloride

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 20 °C 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C 3: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 20 °C 4: hydrogenchloride / 1,4-dioxane; ethyl acetate / 20 °C View Scheme

4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2) → (S)-2-(4-fluoroisoquinoline-5-sulfonamido)-N-(tert-butoxycarbonyl)-N-(3-hydroxypropyl)propylamine

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine; dmap / dichloromethane / 16.75 h / -5 - 30 °C 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 22 h / 20 - 30 °C View Scheme

4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2) → (S)-tert-butyl 4-[(4-fluoroisoquinoline-5-yl)sulfonyl]-3-methyl-1,4-diazepane-1-carboxylate (1360538-86-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine; dmap / dichloromethane / 16.75 h / -5 - 30 °C 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 22 h / 20 - 30 °C 3: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / -5 - 30 °C View Scheme

4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2) → (S)-(-)-1-(4-fluoro-5-isoquinolinesulfonyl)-2-methyl-1,4-homopiperazine (223645-67-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine; dmap / dichloromethane / 16.75 h / -5 - 30 °C 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 22 h / 20 - 30 °C 3: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / -5 - 30 °C 4: hydrogenchloride / ethyl acetate / -5 - 0 °C View Scheme

4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2) → 4-fluoro-5-(tributylstannyl)isoquinoline

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate; sodium sulfite / water / 3 h / 80 °C 2: silver carbonate; bis(tri-t-butylphosphine)palladium(0) / N,N-dimethyl acetamide / 1 h / 140 °C / Inert atmosphere View Scheme

4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2) → C9H5FNO2S(1-)*Na(1+)

Conditions	Yield
With sodium hydrogencarbonate; sodium sulfite In water at 80℃; for 3h;

4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2) + 6-chloroindoline (52537-00-5) → 5-(6-chloroindolin-1-yl)sulfonyl-4-fluoroisoquinoline

Conditions	Yield
With triethylamine In dichloromethane at 25℃; for 12h; Inert atmosphere;	0.2 g

4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2) → 5-(6-chloroindolin-1-yl)sulfonyl-4-fluoro-2-oxidoisoquinolin-2-ium

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 12 h / 25 °C / Inert atmosphere 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 25 °C / Inert atmosphere View Scheme

4-fluoro-5-isoquinolinesulfonyl chloride (194032-33-2) → 5-((6-chloroindolin-1-yl)sulfonyl)-4-fluoroisoquinolin-1-ol

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 12 h / 25 °C / Inert atmosphere 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 25 °C / Inert atmosphere 3: acetic anhydride / 8 h / 110 °C / Inert atmosphere View Scheme

Upstream product

• 1532-97-4 4-bromoisoquinoline 
• 928664-14-6 4-fluoroisoquinoline-5-amine 
• 928664-13-5 4-fluoro-5-nitroisoquinoline 
• 906820-09-5 4-fluoroisoquinoline sulfate 
• 394-67-2 4--fluoroisoquinoline 

Downstream Products

• 223645-67-8 ripasudil 

Relevant academic research and scientific papers

ROCK KINASE INHIBITORS

The present invention relates to compounds that inhibit ROCK activity. In particular, the present invention relates to compounds, pharmaceutical compositions and methods of use, such as methods of inhibiting ROCK activity and methods for treating, for example cerebral cavernous malformation syndrome (CCM) and cardiovascular diseases using the compounds and pharmaceutical compositions of the present invention.

ISOQUINOLINESULFONYL DERIVATIVE AS RHO KINASE INHIBITOR

The present invention discloses a class of isoquinolinesulfonyl derivatives as RHO kinase inhibitors, and pharmaceutical compositions thereof, and relates to pharmaceutically acceptable uses thereof. Specifically, the present invention relates to a compound as represented by formula (I), or a pharmaceutically acceptable salt thereof.

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.

ISOQUINOLINESULFONAMIDE DERIVATIVES AND DRUGS CONTAINING THE SAME AS THE ACTIVE INGREDIENT

This invention relates to isoquinolinesulfonamide derivatives represented by the following formula (1): wherein A represents a linear or branched alkylene group, R1 represents a hydrogen atom, an hydroxyl, alkoxy or alkyl group or the like, R2 represents a hydrogen atom, an alkyl group or the like, R3 represents a hydrogen atom, an alkyl group or the like, and R4 and R5 may be the same or different and individually represent hydrogen atoms or lower alkyl groups; N-oxides and salts thereof; and solvates thereof. This invention is also concerned with pharmaceutical compositions, which contain the derivatives, N-oxides, salts, or solvates. These derivatives, N-oxides, salts, and solvates have viral proliferation inhibiting activities and are useful as AIDS therapeutics.