1228779-96-1

Basic information

• Product Name: 3-nitro-4-((tetrahydro-2H-pyran-4-yl)MethylaMino)benzenesulfonaMide
• Synonyms: 3-nitro-4-((tetrahydro-2H-pyran-4-yl)MethylaMino)benzenesulfonaMide;abt-1－199;3-nitro-4-[(oxan-4-ylmethyl)amino]benzene-1-sulfonamide;3-Nitro-4-[[(tetrahydropyran-4-yl)methyl]amino]benzenesulfonamide;THP-sulfonamide;Venetoclax Intermediate;Benzenesulfonamide, 3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]-;ABT-199 intermedate3
• CAS NO: 1228779-96-1
• Molecular Formula: C₁₂H₁₇N₃O₅S
• Molecular Weight: 315.34548
• EINECS: 1592732-453-0
• Mol File: 1228779-96-1.mol
• Article Data: 21

Chemical Properties

• Boiling Point: 542.0±60.0 °C(Predicted)
• Appearance: /
• Density: 1.412±0.06 g/cm3(Predicted)
• Storage Temp.: 2-8°C(protect from light)
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 9.58±0.60(Predicted)
• CAS DataBase Reference: 3-nitro-4-((tetrahydro-2H-pyran-4-yl)MethylaMino)benzenesulfonaMide(CAS DataBase Reference)
• NIST Chemistry Reference: 3-nitro-4-((tetrahydro-2H-pyran-4-yl)MethylaMino)benzenesulfonaMide(1228779-96-1)
• EPA Substance Registry System: 3-nitro-4-((tetrahydro-2H-pyran-4-yl)MethylaMino)benzenesulfonaMide(1228779-96-1)

Safety Data

• Hazardous Substances Data: 1228779-96-1(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
3-nitro-4-((tetrahydro-2H-pyran-4-yl)MethylaMino)benzenesulfonaMide is used as a reagent for the synthesis of [BTK, PI3K, and JAK-2 inhibitors] for [targeting specific enzymes involved in various diseases and conditions].
In the synthesis of BTK inhibitors, this compound is used as a reagent to develop drugs that can potentially treat conditions such as autoimmune diseases, inflammatory disorders, and certain types of cancer by inhibiting the activity of Bruton's tyrosine kinase (BTK).
In the synthesis of PI3K inhibitors, 3-nitro-4-((tetrahydro-2H-pyran-4-yl)MethylaMino)benzenesulfonaMide is utilized to create compounds that can target the phosphoinositide 3-kinase (PI3K) enzyme, which plays a significant role in cell growth, survival, and metabolism. Inhibiting PI3K can be beneficial in treating various cancers and other diseases associated with the dysregulation of this enzyme.
In the synthesis of JAK-2 inhibitors, this compound is employed to develop drugs that can inhibit Janus kinase 2 (JAK-2), an enzyme involved in the signaling pathways of various cytokines and growth factors. JAK-2 inhibitors can be used to treat conditions such as myeloproliferative neoplasms, autoimmune disorders, and other diseases where JAK-2 activity is abnormally high.
Overall, 3-nitro-4-((tetrahydro-2H-pyran-4-yl)MethylaMino)benzenesulfonaMide is a valuable reagent in the pharmaceutical industry, contributing to the development of novel therapeutic agents targeting key enzymes in various diseases and conditions.

Synthetic route

4-tetrahydropyranmethylamine (130290-79-8) + 4-fluoro-3-nitrobenzenesulfonamide (406233-31-6) → 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1)

Conditions	Yield
With triethylamine In tetrahydrofuran at 20℃; for 5h;	97%
With triethylamine In tetrahydrofuran at 0 - 20℃; for 16h;	95%
With sodium carbonate In isopropyl alcohol at 55 - 65℃; for 4h;	94%

4-tetrahydropyranmethylamine (130290-79-8) + 4-Chloro-3-nitrobenzenesulfonamide (97-09-6) → 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 12h;	91%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 24h; Inert atmosphere; Large scale;	88%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃;	78%

tetrahydro-2H-pyran-4-carbonitrile (4295-99-2) → 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen; ammonia / methanol / 12 h / 40 - 45 °C / 3000.3 - 3750.38 Torr 2: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 h / 55 - 70 °C View Scheme

2-Chloronitrobenzene (88-73-3) → 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: chlorosulfonic acid / 18 h / 20 - 100 °C 1.2: 5 h / -10 - 23 °C 2.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 h / 55 - 70 °C View Scheme

methyl 4-cyanotetrahydro-2H-pyran-4-carboxylate (362703-30-8) → 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydroxide; water / N,N-dimethyl-formamide / 7 h / pH 9 - 11 2: copper(I) oxide / toluene / 7 h / 107 °C 3: hydrogen; ammonia / methanol / 12 h / 40 - 45 °C / 3000.3 - 3750.38 Torr 4: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 h / 55 - 70 °C View Scheme

4-cyanotetrahydro-2H-pyran-4-carboxylic acid → 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: copper(I) oxide / toluene / 7 h / 107 °C 2: hydrogen; ammonia / methanol / 12 h / 40 - 45 °C / 3000.3 - 3750.38 Torr 3: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 h / 55 - 70 °C View Scheme

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoic acid → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromo-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 15h; Inert atmosphere;	100%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 48h;	61.3%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 24h;	80 mg

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid → 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃;	93%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃;	93%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃;	93%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + [2-((1H-pyrrolo [2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid] (1235865-77-6) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (1257044-40-8)

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 3h; Reagent/catalyst; Temperature;	91.4%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 25℃; for 12h; Inert atmosphere; Large scale;	86%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 25℃;	84%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + C40H40ClN5O7S → C51H53ClN8O11S2

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 30 - 35℃;	89%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + C41H43ClN4O5S → C52H56ClN7O9S2

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 30 - 35℃;	88%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + C40H40ClN5O7S → C51H53ClN8O11S2

Conditions	Yield
With dmap; 1,1'-carbonyldiimidazole In dichloromethane at 30 - 35℃;	87%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(tertbutoxycarbonyl)piperazin-1-yl)benzoic acid → C35H41N7O9S

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 30℃; for 0.24h;	80%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 2-bromo-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid → tert-butyl 4-[3-bromo-4-([3-nitroso-4-[(oxan-4-ylmethyl)amino]benzenesulfonyl]carbamoyl)phenyl]piperazine-1-carboxylate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 30℃; for 12h;	79.73%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid hydrochloride → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (1257044-40-8)

Conditions	Yield
Stage #1: 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid hydrochloride With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 25 - 30℃; for 8h; Stage #2: With N,N-dimethylethylenediamine In dichloromethane at 20 - 30℃; for 4h;	70%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 25 - 30℃; for 24h;

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 2-bromo-4-(4-[[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoic acid → 2-bromo-4-(4-[[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-[3-nitro-4-[(oxan-4-ylmethyl)amino]benzenesulfonyl]benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 30℃; for 12h;	65.54%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(13S)-13-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0[3,7]] tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid → 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(13S)-13-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h;	57.72%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperidin-4-yl)benzoic acid → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperidin-4-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	57.3%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 2-[(1H-pyrrolo[2,3-b]pyridine-5-yl)oxy]-4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl]methyl]piperazin-1-yl]benzoic acid sulfate → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (1257044-40-8)

Conditions	Yield
Stage #1: 2-[(1H-pyrrolo[2,3-b]pyridine-5-yl)oxy]-4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl]methyl]piperazin-1-yl]benzoic acid sulfate With triethylamine In dichloromethane at 20 - 25℃; Stage #2: 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide With dmap; diisopropyl-carbodiimide In dichloromethane at 35 - 40℃;	55%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid → 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-([3-nitro-4-[(oxan-4-ylmethyl)amino]benzene]sulfonyl)-2-[13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	54%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	54%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + C33H33(2)H2ClN4O3 → C45H48(2)H2ClN7O7S

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 10h;	53%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + [2-((1H-pyrrolo [2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid] (1235865-77-6) → venetoclax sodium

Conditions	Yield
Stage #1: 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide; [2-((1H-pyrrolo [2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid] With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Stage #2: With sodium hydroxide In methanol at 55 - 60℃; for 2h;	53%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15R)-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzoic acid → 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15R)-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15] ]hexadeca-1(9),2,5,7-tetraen-10-yl]-N-[3-nitro-4-[(oxan-4-ylmethyl)amino]benzenesulfonyl]benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃;	45.84%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid → (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Conditions

Yield

Stage #1: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 4h; Stage #2: 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide With dmap In dichloromethane

42.5%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1‘-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3‘,2’:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoic acid → 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1‘-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3 4-dihydro-2H-pyrrolo[3’,2’:5,6]pyrido[2,3-b][1,4]oxazepin-1 (7H)-yl)benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃;	40%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃;	40%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1‘-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3‘,2’:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoic acid → 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1‘-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3‘,2’:5,6]pyrido[2,3- b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃;	40%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃;	40%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃;	40%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(12,12-difluoro-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl)benzoic acid → 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-3,4-dihydro-2H-pyrrolo[3’,2’:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h;	39.68%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h;	39.68%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzoic acid → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2 H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	39.6%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid TFA salt → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Conditions

Yield

Stage #1: 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 0.166667h; Stage #2: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid TFA salt With 4-methyl-morpholine In dichloromethane at 0 - 20℃; for 16h;

39%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + benzoic acid (65-85-0) → N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Conditions	Yield
With dmap; 1,2-dichloro-ethane In tetrahydrofuran; dichloromethane at 20℃; for 16h;	38%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}(2H8)piperazin-1-yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid → 4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}(2H8)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 10h;	36%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;

Upstream product

• 848821-06-7 4-cyanotetrahydro-2H-pyran-4-carboxylic acid 
• 362703-30-8 methyl 4-cyanotetrahydro-2H-pyran-4-carboxylate 
• 88-73-3 2-Chloronitrobenzene 
• 4295-99-2 tetrahydro-2H-pyran-4-carbonitrile 
• 130290-79-8 4-tetrahydropyranmethylamine 
• 97-09-6 4-Chloro-3-nitrobenzenesulfonamide 
• 406233-31-6 4-fluoro-3-nitrobenzenesulfonamide 

Downstream Products

• 1228779-93-8 4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetra-hydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide 
• 1257044-40-8 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide 
• 1257044-33-9 4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide 

Relevant articles and documents

Development of a Convergent Large-Scale Synthesis for Venetoclax, a First-in-Class BCL-2 Selective Inhibitor

The process development of a new synthetic route leading to an efficient and robust synthetic process for venetoclax (1: the active pharmaceutical ingredient (API) in Venclexta) is described. The redesigned synthesis features a Buchwald-Hartwig amination to construct the core ester 23c in a convergent fashion by connecting two key building blocks (4c and 26), which is then followed by a uniquely effective saponification reaction of 23c using anhydrous hydroxide generated in situ to obtain 2. Finally, the coupling of the penultimate core acid 2 with sulfonamide 3 furnishes drug substance 1 with consistently high quality. The challenges and solutions for the key Pd-catalyzed C-N cross-coupling will also be discussed in detail. The improved synthesis overcomes many of the initial scale-up challenges and was accomplished in 46% overall yield from 3,3-dimethyldicyclohexanone (6), more than doubling the overall yield of the first generation route. The new process was successfully implemented for producing large quantities of 1 with >99% area purity.

CONDENSED HETEROCYCLES AS BCL-2 INHIBITORS

The disclosure includes compounds of Formula (A) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11, h, j, m, n, k, v, s, g, V, W, L, Z1 Q1, Q2, Q3, Q4, Q5, Q6, and Q7, are defined herein. Also disclosed is a method for treating a neoplastic disease, an autoimmune disease, or a neorodegenerative disease with these compounds.

1H-PYRROLO[2,3-B]PYRIDINE DERIVATIVES AS BCL-2 INHIBITORS FOR THE TREATMENT OF NEOPLASTIC AND AUTOIMMUNE DISEASES

The present invention relates to lH-pyrrolo[2,3-b]pyridine derivatives and related compounds as BCL-2 inhibitors for treating neoplastic, autoimmune or neurodegenerative diseases. The present description discloses the synthesis and characterisation of exemplary compounds as well as pharmacological data thereof (e.g. pages 162 to 233; examples 1 to 8; table; compound examples cpd-1 to cpd-135; biological examples 1 to 4).

HOT MELT EXTRUDED SOLID DISPERSIONS CONTAINING A BCL2 INHIBITOR

A pro-apoptotic solid dispersion comprises, a Bcl -2 family protein inhibitory compound of Formula A as defined herein, dispersed in a solid matrix that comprises (a) a pharmaceutically acceptable water-soluble polymeric carrier, and (b) a pharmaceutically acceptable surfactant. A process for preparing such a solid dispersion comprises subjecting to elevated temperature the compound of Formula A, the water-soluble polymeric carrier, and the surfactant to provide an extrudable semi-solid mixture; extruding the semi-solid mixture; and cooling the resulting extrudate to provide a solid matrix comprising the polymeric carrier, and the surfactant and having the compound dispersed in essentially non-crystalline form therein. The solid dispersion is suitable for oral administration to a subject in need thereof for treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl -2 family proteins, for example cancer or an immune or autoimmune disease.

Discovery of potent and selective Bcl-2 inhibitors with acyl sulfonamide skeleton

The antiapoptotic protein B-cell lymphoma 2 (Bcl-2), overexpressed in many tumor cells, is an attractive target for potential small molecule anticancer drug discovery. Herein, a series of novel derivatives with acyl sulfonamide skeleton was designed, synthesized, and evaluated as Bcl-2 inhibitors by means of bioisosteric replacement. Among them, compound 24g demonstrated equal efficient inhibition activity against RS4;11 cell line compared to positive control ABT-199. Moreover, it showed improved selectivity for Bcl-2/Bcl-xL inhibitory effects, the result of which was consistent with platelet toxicity studies. In vitro and in vivo pharmacokinetic properties of compound 24g had a significantly improved profiles. Taken together, those results suggested it as a promising candidate for development of novel therapeutics targeting Bcl-2 in cancer.

BCL-2 INHIBITORS

The disclosure includes compounds of Formula (A), (A) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11, h, j, m, n, k, v, s, g, V, W, L, Z1, Q1, Q2, Q3, Q4, Q5, Q6, and Q7, are defined herein. Also disclosed is a method for treating a neoplastic disease, an autoimmune disease, or a neorodegenerative disease with these compounds.

BCL-2 INHIBITORS

The disclosure includes compounds of Formula (I), (I) wherein Z, Q1, Q3, Q4, Q5, Q6, Q7, R0, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, g, k, m, n, s, v, j, L, Z1, and, W are defined herein. Also disclosed is a method for treating a neoplastic disease and autoimmune disease with these compounds.

Bcl-2 INHIBITORS

Disclosed herein is a compound of Formula (I) for inhibiting Bcl-2 and treating disease associated with undesirable bcl-2 activity (Bcl-2 related diseases), a method of using the compounds disclosed herein for treating dysregulated apoptotic diseases including cancers and treating autoimmune disease, and a pharmaceutical composition comprising the same.

Efficient synthesis of carbon-11 labelled acylsulfonamides using [11C]CO carbonylation chemistry

Herein, a novel method for carbon-11 labeling of acyl sulfonamides by a one-step insertive [11C]CO carbonylative cross-coupling reaction between aryl halides and sulfonamides is presented. Various model compounds as well as drug molecules LY573636 (tasisulam) and ABT-199 were obtained in excellent yields. This method provides a valuable and widely applicable contribution to the continuously expanding radiochemical toolbox for PET research.

Solid dispersions containing an apoptosis-inducing agent

A pro-apoptotic solid dispersion comprises, in essentially non-crystalline form, a Bcl-2 family protein inhibitory compound of Formula I as defined herein, dispersed in a solid matrix that comprises (a) a pharmaceutically acceptable water-soluble polymeric carrier and (b) a pharmaceutically acceptable surfactant. A process for preparing such a solid dispersion comprises dissolving the compound, the polymeric carrier and the surfactant in a suitable solvent, and removing the solvent to provide a solid matrix comprising the polymeric carrier and the surfactant and having the compound dispersed in essentially non-crystalline form therein. The solid dispersion is suitable for oral administration to a subject in need thereof for treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl-2 family proteins, for example cancer.