72811-73-5

Basic information

• Product Name: 4-(3'-Methylphenyl)amino-3-pyridinesulfonamide
• Synonyms: 4-(-3-METHYLPHENYL)AMINO-3-PYRIDINESULFONAMIDE;4-(3'-METHYLPHENYL)AMINO-3-PYRIDINESULFONAMIDE;3-SULFONAMIDO-4-(3-METHYLANILINO)-PYRIDINE;SPECS AJ-333/25006115;4-(3-METHYLPHENYL)AMINO-3-PYRIDINESULFONAMIDE (SMPAP);4-[3-Methyl phenyl] amino-3-pyridine sulphonamide;Torasemide intermediate;[4-(3-Methylphenyl)amino]pyrid
• CAS NO: 72811-73-5
• Molecular Formula: C₁₂H₁₃N₃O₂S
• Molecular Weight: 263.32
• EINECS: 1806241-263-5
• Product Categories: INTERMEDIATESOFTORASEMIDE;Pyridines derivates;(intermediate of torasemide);Pyridines;Torsemide;Aromatics;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 72811-73-5.mol

Chemical Properties

• Melting Point: 162-164?C
• Boiling Point: 475.8 °C at 760 mmHg
• Flash Point: 241.5 °C
• Appearance: /
• Density: 1.357 g/cm³
• Vapor Pressure: 3.23E-09mmHg at 25°C
• Refractive Index: 1.641
• Storage Temp.: Refrigerator
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 9.53±0.60(Predicted)
• BRN: 5438165
• CAS DataBase Reference: 4-(3'-Methylphenyl)amino-3-pyridinesulfonamide(CAS DataBase Reference)
• NIST Chemistry Reference: 4-(3'-Methylphenyl)amino-3-pyridinesulfonamide(72811-73-5)
• EPA Substance Registry System: 4-(3'-Methylphenyl)amino-3-pyridinesulfonamide(72811-73-5)

Safety Data

• Hazard Codes: Xi
• Statements: 36
• Safety Statements: 26
• Hazardous Substances Data: 72811-73-5(Hazardous Substances Data)

Usage

Chemical Properties

White to Off-White Solid

Uses

Torasemide intermediate.

InChI:InChI=1/C12H13N3O2S/c1-9-3-2-4-10(7-9)15-11-5-6-14-8-12(11)18(13,16)17/h2-8H,1H3,(H,14,15)(H2,13,16,17)

Synthetic route

4-chloropyridine-3-sulphonamide (33263-43-3) + 1-amino-3-methylbenzene (108-44-1) → 3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5)

Conditions	Yield
In methanol at 39.85℃; for 3h;	96.5%
In propan-1-ol for 5h; Heating;
In water at 80 - 90℃; for 1 - 1.5h; Product distribution / selectivity;
Stage #1: 4-chloropyridine-3-sulphonamide; 1-amino-3-methylbenzene In water for 0.5h; Heating / reflux; Stage #2: With sodium hydroxide In water at 20 - 35℃; Stage #3: With sulfuric acid In water Product distribution / selectivity;

4-chloro-3-pyridinesulfonamide hydrochloride (777854-85-0) + 1-amino-3-methylbenzene (108-44-1) → 3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5)

Conditions	Yield
Stage #1: 4-chloro-3-pyridinesulfonamide hydrochloride; 1-amino-3-methylbenzene In water at 90℃; for 3h; Stage #2: With sodium hydrogencarbonate In water at 20℃; pH=7 - 8;	92%

3-Iodotoluene (625-95-6) + 3-sulfonamido-4-aminopyridine (75903-62-7) → 3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5)

Conditions	Yield
With copper; potassium carbonate In butan-1-ol	53.1%

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) + Isopropyl isocyanate (1795-48-8) → torasemide crude

Conditions	Yield
Stage #1: 3-sulfonamido-4-(3'-methylphenyl) aminopyridine With sodium hydride In tetrahydrofuran; toluene at 5 - 20℃; for 16h; Stage #2: Isopropyl isocyanate In tetrahydrofuran; toluene at 20℃; Stage #3: Isopropyl isocyanate With sodium hydride; acetic acid more than 3 stages;	100%

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) + Isopropyl isocyanate (1795-48-8) → torasemide (56211-40-6)

Conditions	Yield
Stage #1: 3-sulfonamido-4-(3'-methylphenyl) aminopyridine; Isopropyl isocyanate With potassium carbonate In diethylene glycol dimethyl ether; water at 65 - 70℃; for 0.583333h; Stage #2: With acetic acid In diethylene glycol dimethyl ether; water at 20 - 25℃; for 3h; pH=5.3 - 5.7;	96.5%
Stage #1: 3-sulfonamido-4-(3'-methylphenyl) aminopyridine; Isopropyl isocyanate With sodium hydroxide In acetone at 20 - 30℃; Stage #2: With acetic acid In water; acetone at 20 - 25℃; for 0.25h; pH=5.3 - 5.7;	96%
Stage #1: 3-sulfonamido-4-(3'-methylphenyl) aminopyridine; Isopropyl isocyanate With sodium hydroxide In acetone at 20 - 30℃; Stage #2: With acetic acid In water; acetone at 20 - 25℃; for 0.25h; pH=5.5;	96%

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) + Isopropyl isocyanate (1795-48-8) → torsemide sodium

Conditions	Yield
With sodium hydroxide In acetone at 5 - 20℃; for 2h; Reagent/catalyst;	94.5%

phenyl N-isopropylcarbamate (17614-10-7) + 3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → torasemide (56211-40-6)

Conditions	Yield
Stage #1: phenyl N-isopropylcarbamate; 3-sulfonamido-4-(3'-methylphenyl) aminopyridine With triethylamine In water; acetone for 3h; Heating / reflux; Stage #2: With sodium hydroxide In water at 20 - 25℃; Stage #3: With sulfuric acid In water; acetone at 50 - 55℃; for 1h; Product distribution / selectivity;	87.8%
Stage #1: phenyl N-isopropylcarbamate; 3-sulfonamido-4-(3'-methylphenyl) aminopyridine With sodium hydroxide In water at 90 - 100℃; for 5h; Stage #2: With sulfuric acid In water at 20 - 70℃; for 1h; Product distribution / selectivity;	85%
Stage #1: 3-sulfonamido-4-(3'-methylphenyl) aminopyridine With sodium hydroxide In water at 20 - 35℃; Stage #2: phenyl N-isopropylcarbamate In water; acetone at 50 - 60℃; for 20h; Stage #3: With sulfuric acid In water at 15 - 50℃; for 3h; pH=7.0; Product distribution / selectivity;

chloroformic acid ethyl ester (541-41-3) + 3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → [4-(3-methyl-anilino)-pyridine-3-sulfonyl]-carbamic acid ethyl ester (72810-57-2)

Conditions	Yield
With pyridine for 0.333333h; Heating;	75%
In tetrahydrofuran for 8h; Ambient temperature;

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) + N-cyano-N'-isopropyl-S-methylcarbamimidothioate (5848-27-1) → N2-cyano-N1-isopropyl-N3-<4-(3-methylphenylamino)-3-pyridylsulfonyl>guanidine

Conditions	Yield
With sodium hydroxide In 1,4-dioxane; N,N-dimethyl-formamide for 6h; Heating;	37%

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → C23H28N4O3S

Conditions	Yield
Multi-step reaction with 2 steps 1: 75 percent / pyridine / 0.33 h / Heating 2: 37 percent / toluene / 5 h / Heating View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → C15H18N4O3S (72811-70-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / 110 °C View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → C16H18N4O3S (77281-86-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / Heating View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → C17H22N4O3S (72811-16-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / 110 °C View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → C19H22N4O3S (72810-99-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / Heating View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → 4-m-Tolylamino-pyridine-3-sulfonic acid (pyrrolidine-1-carbonyl)-amide (72811-47-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / Heating View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → C17H22N4O3S (77281-87-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / Heating View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → C18H24N4O3S (72811-41-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / Heating View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → C18H24N4O3S (72810-97-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / Heating View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → C17H22N4O4S (72826-74-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / Heating View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → 4-m-Tolylamino-pyridine-3-sulfonic acid (piperidine-1-carbonyl)-amide (72811-64-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / Heating View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → C19H26N4O3S (72811-63-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / Heating View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → C20H20N4O3S (77281-91-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / Heating View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → C19H24N4O3S (77281-89-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / Heating View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → 4-m-Tolylamino-pyridine-3-sulfonic acid (4-methyl-piperidine-1-carbonyl)-amide (72811-19-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / Heating View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → 4-m-Tolylamino-pyridine-3-sulfonic acid (3-methyl-piperidine-1-carbonyl)-amide (72811-12-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / Heating View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → 4-m-Tolylamino-pyridine-3-sulfonic acid (morpholine-4-carbonyl)-amide (72811-03-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / Heating View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → 4-m-Tolylamino-pyridine-3-sulfonic acid (azepane-1-carbonyl)-amide (72811-02-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / Heating View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → C21H22N4O3S (72811-01-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / Heating View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → 4-m-Tolylamino-pyridine-3-sulfonic acid (3,5-dimethyl-piperidine-1-carbonyl)-amide (72811-68-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / Heating View Scheme

3-sulfonamido-4-(3'-methylphenyl) aminopyridine (72811-73-5) → C18H18N4O4S (72811-48-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Ambient temperature 2: 0.4 nm molecular sieves / toluene / Heating View Scheme

Upstream product

• 33263-43-3 4-chloropyridine-3-sulphonamide 
• 108-44-1 1-amino-3-methylbenzene 
• 777854-85-0 4-chloro-3-pyridinesulfonamide hydrochloride 
• 625-95-6 3-Iodotoluene 
• 75903-62-7 4-aminopyridine-3-sulfonamide 

Downstream Products

• 72810-57-2 [4-(3-methyl-anilino)-pyridine-3-sulfonyl]-carbamic acid ethyl ester 
• 56211-40-6 torasemide 
• 72811-70-2 C₁₅H₁₈N₄O₃S 
• 77281-86-8 C₁₆H₁₈N₄O₃S 
• 72811-16-6 C₁₇H₂₂N₄O₃S 
• 72810-99-2 C₁₉H₂₂N₄O₃S 
• 72811-47-3 4-m-Tolylamino-pyridine-3-sulfonic acid (pyrrolidine-1-carbonyl)-amide 
• 77281-87-9 C₁₇H₂₂N₄O₃S 
• 72811-41-7 C₁₈H₂₄N₄O₃S 
• 72810-97-0 C₁₈H₂₄N₄O₃S 
• 72826-74-5 C₁₇H₂₂N₄O₄S 
• 72811-64-4 4-m-Tolylamino-pyridine-3-sulfonic acid (piperidine-1-carbonyl)-amide 
• 72811-63-3 C₁₉H₂₆N₄O₃S 
• 77281-91-5 C₂₀H₂₀N₄O₃S 

Relevant articles and documents

Supramolecular structures of three isomeric 4-(methylphenylamino)-pyridine- 3-sulfonamides

The structures of the three title isomers, namely 4-(2-methylanilino) pyridine-3-sulfonamide, (I), 4-(3-methylanilino)pyridine-3-sulfonamide, (II), and 4-(4-methylanilino)-pyridine-3-sulfonamide, (III), all C12H 13N3O2S, differ in their hydrogen-bonding arrangements. In all three molecules, the conformation of the 4-aminopyridine-3-sulfonamide moiety is conserved by an intramolecular N-H...O hydrogen bond and a C-H...O interaction. In the supramolecular structures of all three isomers, similar C(6) chains are formed via intermolecular N-H...N hydrogen bonds. N-H...O hydrogen bonds lead to C(4) chains in (I), and to R22(8) centrosymmetric dimers in (II) and (III). In each isomer, the overall effect of all hydrogen bonds is to form layer structures.

PREPARATION OF TORASEMIDE

The stable polymorphic form of torasemide, Modification I, is prepared from other, less stable torasemide forms, by forming a solution of the starting polymorphic form of torasemide in water and methanol, stirring for at least 20 hours and then phase separating the solid torasemide modification I from the liquid medium.

PROCESS FOR THE PREPARATION OF HIGHLY PURE TORSEMIDE

The present invention provides a novel process for the preparation of highly pure torsemide [1] by reacting of 4-m-tolylamino-3-pyridinesulfonamide [2] with phenyl isopropylcarbamate in the presence of lithium base (F I, II). The present invention also provides a novel intermediate - torsemide lithium, also in hydrate or solvate form - which is a stable, solid compound, and may be simply isolated from the reaction mixture to give after acidification practically pure torsemide [1] without further purification steps.

Preparation of derivative of 3-sulfonamido-4-phenylaminopyridine

This invention relates to the preparation of 3-sulfonamido-4-arylaminopyridines by heating a 3-sulfonamido-4-aminopyridine with an aryl halide in the presence of an alkaline compound, a copper-containing agent and in the presence of a polar protic solvent.